Beruflich Dokumente
Kultur Dokumente
for
Physiotherapy
Pharmacology
for
Physiotherapy
Second Edition
Padmaja Udaykumar
Professor and Head
Department of Pharmacology
Fr Muller Medical College
Mangalore, Karnataka, India
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or
transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise,
without the prior written permission of the author and the publisher.
This book has been published in good faith that the material provided by author is original. Every
effort is made to ensure accuracy of material, but the publisher, printer and author will not be held
responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled
under Delhi jurisdiction only.
ISBN 978-93-80704-67-8
Textbook is the most important companion, tool and light of a learning student to lead him, to shape
him, enlighten him to perfect himself in the chosen subject of his studies. So it should be reader
friendly, descriptive and analytical, to reach those goals, to fit into the mind of the learner. It should
also be tailored to the needs of the student to pass his examination, which also is one of the primary
goals of a student.
Pharmacology to many, including me, is one of the tough subjects, to learn amongst the medical
curriculum. Most of the textbooks in pharmacology have been written, tailored to the needs of a
medical student. Dr Padmaja Udaykumar in her own inimitable style has penned this textbook fully
looking into the needs of a physiotherapy student. Physiotherapy is one of the most dynamic fields in
medicine today to put back the patient to his physical perfection and the student ought to know the
pharmacodynamics of the musculoskeletal and neurovascular systems. This book has met all these
goals and I find it useful to an orthopedic and physical medicine postgraduate student as well.
I have known Dr Padmaja for many years. Her tenacity of purpose, vision and enthusiasm has
culminated in yet another masterpiece. She is a source of inspiration to the younger generation for
academic excellence.
I am sure this textbook will be of immense help to its user and I strongly recommend it, especially
to physiotherapy students.
Dr M Shantharam Shetty
Vice-Chancellor and Professor of Orthopaedics
KS Hegde Medical Academy, Nitte University
Mangalore, Karnataka, India
Preface to the Second Edition
The expansion of pharmacology in the last few years has been phenomenal. Basic knowledge of
commonly used drugs is essential for all those who are involved in patient care. The depth of
pharmacology knowledge required for physiotherapists has now been better understood. This has
prompted changes in syllabus in several universities for physiotherapy. To keep pace with these
changes, this edition has been published. In this edition, several new topics relating to muscle nerve
pathophysiology and geriatric pharmacology have been added as required by the syllabus of some
universities and unnecessary information has been pruned. The book has been tailored to the needs of
physiotherapy students.
Padmaja Udaykumar
Preface to the First Edition
Pharmacology is a science that is rapidly growing. Basic knowledge of pharmacology is required for
all those who deal with patients. Since there is no standard textbook meant exclusively for
physiotherapy students, they are faced with the hardship of having to refer medical pharmacology
books. Such volume and depth of pharmacology is unnecessary for physiotherapists and also difficult
to comprehend. Hence this book is written to make pharmacology simple for physiotherapy students.
The presentation has been simple so that the students easily understand the subject. Guidelines of the
University syllabus has been followed. More importance has been given for topics like analgesics,
skeletal muscle relaxants and other musculoskeletal disorders which are emphasized for physiotherapy
students. Syllabuses of some universities have recommended topics like ‘drugs and exercise’,
‘vasoconstrictors and vasodilators’ for physiotherapy students. They have also been discussed briefly.
Padmaja Udaykumar
Acknowledgments
I wish to place on record my sincere thanks to Dr Annappa Kulal for his suggestions. I am thankful
to my colleagues Dr Princy Palatty, Dr Prasanna Lakshmi, Dr Vijayalakshmi, Dr Raghvendra Baliga,
and Dr Chandrashekhar, Dr Manohar Revankar and Ms Rojin for their encouragement.
I owe a special note of thanks to my husband Prof Udaykumar K for his constant encouragement
and valuable suggestions, which made this work possible.
I also wish to thankfully acknowledge the prompt and meticulous work of M/s Jaypee Brothers
Medical Publishers (P) Ltd, New Delhi.
Contents
INTRODUCTION AND SOURCES OF DRUGS like’ and dilution enhances the action of drugs.
Thus, several systems of therapeutics were
Pharmacology is the science that deals with the introduced, of which only few survived. The basic
study of drugs and their interaction with the living reason for failure of many systems is that man’s
systems. concepts about diseases were incorrect and
Early man recognized the benefits and toxic baseless in those days. By the end of the 17th
effects of many plants and animal products. century the importance of experimentation and
India’s earliest pharmacological writings are from observation became clear and many physicians
the ‘Vedas.’ An ancient Indian physician Charaka applied these to the traditional drugs. Francois
and then Sushruta and Vagbhata described many Magendie and Claude-Bernard popularized the
herbal preparations included in ‘Ayurveda’ use of animal experiments to understand the
(meaning the science of life). James Gregory effects of drugs. The development of physiology
recommended harsh and dangerous remedies like also helped in the better understanding of
blood-letting, emetics and purgatives to be used pharmacology. The last century has seen a rapid
until the symptoms of the disease subsided (such growth of the subject with new concepts and
remedies often resulted in fatality). This was called techniques being introduced.
‘Allopathy’ meaning the other suffering. This
word, still being used for the modern system of
DEFINITIONS
medicine, is a misnomer. To counter this system,
Hannemann introduced the system of Homoeo- The word pharmacology is derived from the Greek
pathy meaning similar suffering in the early 19th word—Pharmacon meaning an active principle or
century. The principles of this include ‘like cures drug and logos meaning a discourse or study.
2 Pharmacology for Physiotherapy
ENTERAL ROUTE (ORAL INGESTION) minimizes chances of the drug getting into larynx
or behind the epiglottis. Recumbent patient
This is the most common, oldest and safest route
should not be given drugs orally as some drugs
of drug administration. The large surface area of
may remain in the esophagus due to the absence
the gastrointestinal tract, the mixing of its contents
of gravitational force which facilitates the passage
and the differences in pH at different parts of the
of the drug into the stomach. Such drugs can
gut facilitate effective absorption of the drugs given
damage the esophageal mucosa, e.g. iron salts,
orally. However, the acid and enzymes secreted
tetracyclines.
in the gut and the biochemical activity of the
bacterial flora of the gut can destroy some drugs
Enteric Coated Tablets
before they are absorbed.
Some tablets are coated with substances like
Advantages cellulose-acetate, phthalate, gluten, etc. which are
1. Safest route. not digested by the gastric acid but get disinte-
2. Most convenient. grated in the alkaline juices of the intestine. This
3. Most economical. will:
4. Drugs can be self-administered. 1. Prevent gastric irritation.
5. Non-invasive route. 2. Avoid destruction of the drug by the stomach.
Disadvantages 3. Provide higher concentration of the drug in
1. Onset of action is slower as absorption needs the small intestine.
time. 4. Retard the absorption, and thereby prolong
2. Irritant and unpalatable drugs cannot be the duration of action. But if the coating is
administered. inappropriate, the tablet may be expelled
3. Some drugs may not be absorbed due to certain without being absorbed at all. Similarly,
physical characteristics, e.g. streptomycin. controlled-release or sustained-release
4. Irritation to the gastrointestinal tract may lead preparations are designed to prolong the rate
to vomiting. of absorption and thereby the duration of
5. There may be irregularities in absorption. action of drugs. This is useful for short-acting
6. Some drugs may be destroyed by gastric juices, drugs.
e.g. insulin. Advantages
7. Cannot be given to unconscious and unco- • Frequency of administration may be reduced.
operative patients. • Therapeutic concentration may be maintained
8. Some drugs may undergo extensive first pass specially when nocturnal symptoms are to be
metabolism in the liver. treated.
To overcome some of the disadvantages,
Disadvantages
irritants are given in capsules, while bitter drugs
• There may be ‘failure of the preparation’
are given as sugar coated tablets. Sometimes drugs
resulting in release of the entire amount of the
are coated with substances like synthetic resins,
drug in a short-time leading to toxicity.
gums, sugar, coloring and flavoring agents
• It is more expensive.
making them more acceptable.
Certain precautions are to be taken during oral
PARENTERAL ROUTE
administration of drugs—capsules and tablets
should be swallowed with a glass of water with Routes of administration other than the enteral
the patient in upright posture either sitting or stan- (intestinal) route are known as parenteral routes.
ding. This facilitates passage of the tablet into the Here the drugs are directly delivered into tissue
stomach and its rapid dissolution. It also fluids or blood.
4 Pharmacology for Physiotherapy
Transdermal Adhesive Units (See page 6). site-specific delivery of drugs may be possible with
the help of liposomes.
Prodrug is an inactive form of the drug which gets
metabolized to the active derivative in the body. A
prodrug may overcome some of the disadvantages PHARMACOKINETICS
of the conventional forms of drug administration, Pharmacokinetics is the study of the absorption,
e.g. dopamine does not cross the BBB; levodopa, a distribution, metabolism and excretion of drugs,
prodrug crosses the BBB and is then converted i.e. the movement of the drugs into, within and
to dopamine in the CNS. Prodrugs may also be out of the body. For a drug to produce its specific
used to have longer duration of action, e.g. response, it should be present in adequate
Bacampicillin (a prodrug of ampicillin) is longer concentrations at the site of action. This depends
acting. on various factors apart from the dose. Once the
drug is administered, it is absorbed, i.e. enters the
Osmotic pumps are small tablet shaped units blood, is distributed to different parts of the body,
consisting of the drug and an osmotic substance reaches the site of action, is metabolized and
placed in two chambers. The osmotic layer swells excreted (Fig. 1.1). All these processes involve
and pushes the drug slowly out of a small hole. passage of the drug molecules across various
Iron and prazosin are available in this form. barriers—like the intestinal epithelium, cell memb-
rane, renal filtering membrane, capillary barrier
Computerized miniature pumps: These are
and so on. To cross these barriers the drug has to
programmed to release drugs at a definite rate
cross the cell membrane or pass in-between the
either continuously as in case of insulin or
epithelial or endothelial cells.
intermittently in pulses as in case of GnRH.
The cell membrane/biological membrane is
Various methods of drug targeting are tried
made up of two layers of phospholipids with
especially for anticancer drugs to reduce toxicity.
intermingled protein molecules (Fig. 1.2). All lipid
Monoclonal antibodies against the tumor specific soluble substances get dissolved in the cell
antigens are used to deliver anticancer drugs to membrane and readily permeate into the cells. The
specific tumor cells. junctions between epithelial or endothelial cells
have pores through which small water-soluble
Liposomes are phospholipids suspended in molecules can pass. Movement of some specific
aqueous vehicles to form minute vesicles. Drugs substances is regulated by special carrier proteins.
encapsulated in liposomes are taken up mainly The passage of drugs across biological
by the reticuloendothelial cells of the liver and membranes involves processes like passive
are also concentrated in malignant tumors. Thus, (filtration, diffusion) and active transport.
absorbed faster than solids. Delay in should be kept large, e.g. anthelmintics like
disintegration and dissolution as with poorly bephenium hydroxynaphthoate.
water-soluble drugs like aspirin, result in 4. Lipid solubility Lipid soluble drugs are
delayed absorption. absorbed faster and better by dissolving in
2. Formulation Pharmaceutical preparations the phospholipids of the cell membrane.
are formulated to produce desired 5. pH and ionization Ionized drugs are poorly
absorption. Inert substances used with drugs absorbed while unionized drugs are lipid
as diluents like starch and lactose may soluble and are well absorbed. Most drugs
sometimes interfere with absorption. are weak electrolytes and ionise according
3. Particle size Small particle size is important to pH. Thus acidic drugs remain unionized
for better absorption of drugs. Drugs like in acidic medium of the stomach and are
corticosteroids, griseofulvin, digoxin, aspirin rapidly absorbed, e.g. aspirin, barbiturates.
and tolbutamide are better absorbed when Basic drugs are unionized when they reach
given as small particles. On the other hand, the alkaline medium of intestine from where
when a drug has to act on the gut and its they are rapidly absorbed, e.g. pethidine,
absorption is not desired, then particle size ephedrine.
General Pharmacology 11
Strong acids and bases are highly ionized glycerine, propranolol, salbutamol. But for drugs
and therefore poorly absorbed, e.g. strepto- that undergo extensive first pass metabolism, the
mycin. route of administration has to be changed, e.g.
6. Area and vascularity of the absorbing isoprenaline, hydrocortisone, insulin.
surface: The larger the area of absorbing
First pass metabolism
surface and more the vascularity—better is
• is metabolism of a drug during its first passage
the absorption. Thus most drugs are
through gut wall and liver
absorbed from small intestine because it has
• reduces bioavailability
a large surface area for absorption and good
vascularity. • extent of metabolism depends on the drug and
7. Gastrointestinal motility: individuals
Gastric emptying time—if gastric emptying is • consequences:
faster, the passage of the drug to the intestines — dose has to be increased for some drugs like
is quicker and hence absorption is faster. propranolol
— route has to be changed for some others like
Intestinal motility—when highly increased as
hydrocortisone
in diarrheas, drug absorption is reduced.
8. Presence of food: In the stomach delays • Examples: morphine, chlorpromazine, nitro-
glycerine, verapamil, testosterone, insulin,
gastric emptying, dilutes the drug and delays
lignocaine
absorption. Drugs may form complexes with
food constituents and such complexes are
poorly absorbed, e.g. tetracyclines chelate Bioavailability
calcium present in food. Moreover, certain Bioavailability is the fraction of the drug that
drugs like ampicillin, roxithromycin and reaches the systemic circulation following
rifampicin are well-absorbed only on empty administration by any route. Thus for a drug given
stomach. intravenously, the bioavailability is 100 percent.
9. Metabolism: Some drugs may be degraded On IM/SC injection, drugs are almost completely
in the GI tract, e.g. nitroglycerine, insulin. absorbed while by oral route, bioavailability may
Such drugs should be given by alternate be low due to incomplete absorption and first pass
routes. metabolism. Infact all the factors which influence
10. Diseases of the gut like malabsorption and the absorption of a drug also alter bioavailability.
achlorhydria result in reduced absorption of
drugs. Bioequivalence
First pass metabolism is the metabolism of a Comparison of bioavailability of different
drug during its passage from the site of absorption formulations of the same drug is the study of
to the systemic circulation. It is also called bioequivalence. Often oral formulations con-
presystemic metabolism or first pass effect and is taining the same amount of a drug from different
an important feature of oral route of administ- manufacturers may result in different plasma
ration. Drugs given orally may be metabolized in concentrations, i.e. there is no bioequivalence.
the gut wall and in the liver before reaching the Such differences occur with poorly soluble, slowly
systemic circulation. The extent of first pass absorbed drugs mainly due to differences in the
metabolism differs from drug to drug and among rate of disintegration and dissolution. Variation
individuals, from partial to total inactivation. in bioavailability (nonequivalence) can result in
When it is partial, it can be compensated by giving toxicity or therapeutic failure in drugs that have
higher dose of the particular drug, e.g. nitro- low safety margin like digoxin and drugs that need
12 Pharmacology for Physiotherapy
precise dose adjustment like anticoagulants and example, indomethacin displaces warfarin
corticosteroids. For such drugs, in a given patient, from protein binding sites leading to increased
the preparations from a single manufacturer warfarin levels.
should be used. 5. Chronic renal failure and chronic liver disease
result in hypoalbuminemia with reduced
DISTRIBUTION
protein binding of drugs.
After a drug reaches the systemic circulation, it
Some highly protein bound drugs
gets distributed to other tissues. It should cross
several barriers before reaching the site of action. Warfarin Tolbutamide Phenytoin
Like absorption, distribution also involves the Frusemide Clofibrate Sulfonamides
same processes, i.e. filtration, diffusion and Diazepam Salicylates Phenylbutazone
Indomethacin
specialized transport. Various factors determine
the rate and extent of distribution, viz lipid solu-
bility, ionization, blood flow and binding to Tissue Binding
plasma proteins and cellular proteins. Unionized
lipid soluble drugs are widely distributed Some drugs get bound to certain tissue consti-
throughout the body. tuents because of special affinity for them. Tissue
binding delays elimination and thus prolongs
Plasma Protein Binding duration of action of the drug. For example, lipid
soluble drugs are bound to adipose tissue. Tissue
On reaching the circulation most drugs bind to binding also serves as a reservoir of the drug.
plasma proteins; acidic drugs bind mainly
albumin and basic drugs to alpha-acid glyco- Redistribution
protein. The free or unbound fraction of the drug
When highly lipid soluble drugs are given intra-
is the only form available for action, metabolism
venously or by inhalation, they get rapidly
and excretion while the protein bound form serves
distributed into highly perfused tissues like brain,
as a reservoir. The extent of protein binding varies
heart and kidney. But soon they get redistributed
with each drug, e.g. warfarin is 99 percent and
into less vascular tissues like the muscle and fat
morphine is 35 percent protein bound while
resulting in termination of the action of these
binding of ethosuximide and lithium is 0 percent,
drugs. The best example is the intravenous
i.e. they are totally free.
anesthetic thiopental sodium which induces
anesthesia in 10-20 seconds but the effect stops in
Clinical Significance of Plasma Protein Binding
5-15 minutes due to redistribution.
1. Only free fraction is available for action,
metabolism and excretion. When the free drug Blood-brain Barrier (BBB)
levels fall, bound drug is released.
The endothelial cells of the brain capillaries lack
2. Protein binding serves as a store (reservoir) of
intercellular pores and instead have tight
the drug and the drug is released when free
junctions. Moreover, glial cells envelope the
drug levels fall. capillaries and together these form the BBB. Only
3. Protein binding prolongs duration of action lipid soluble, unionized drugs can cross this BBB.
of the drug. During inflammation of the meninges, the barrier
4. Many drugs may compete for the same binding becomes more permeable to drugs, e.g. penicillin
sites. Thus one drug may displace another from readily penetrates during meningitis. The barrier
the binding sites resulting in toxicity. For is weak at some areas like chemoreceptor triggor
General Pharmacology 13
zone (CTZ), posterior pituitary and parts of hypo- are easily excreted through the kidneys. Some
thalamus and allows some compounds to diffuse. drugs may be excreted largely unchanged in the
urine, e.g. frusemide, atenolol.
Placental Barrier
Site
Lipid soluble, unionized drugs readily cross the
placenta while lipid insoluble drugs cross to a The most important organ of biotransformation is
much lesser extent. Thus drugs taken by the mother the liver. But drugs are also metabolized by the
can cause several unwanted effects in the fetus. kidney, gut mucosa, lungs, blood and skin.
The chemical reactions of biotransformation enzymes can be enhanced by certain drugs and
can take place in two phases (Fig. 1.4). environmental pollutants. This is called enzyme
1. Phase I (Non-synthetic reactions) induction and this process speeds up the meta-
2. Phase II (Synthetic reactions). bolism of the inducing drug itself and other drugs
metabolized by the microsomal enzymes, e.g.
Phase I reactions convert the drug to a more polar phenobarbitone, rifampicin, alcohol, cigarette
metabolite by oxidation, reduction or hydrolysis. smoke, DDT, griseofulvin, carbamazepine and
Oxidation reactions are the most important phenytoin are some enzyme inducers.
metabolizing reactions, mostly catalyzed by Enzyme induction can result in drug inter-
mono-oxygenases present in the liver. If the actions when drugs are given together because
metabolite is not sufficiently polar to be excreted, one drug may enhance the metabolism of the other
they undergo phase II reactions. drug resulting in therapeutic failure.
ketoconazole, ciprofloxacin and verapamil are Drugs may compete for the same transport system
some enzyme inhibitors. resulting in prolongation of action of each other,
e.g. penicillin and probenecid.
EXCRETION
Passive tubular reabsorption: Passive diffusion
Drugs are excreted from the body after being of drug molecules can occur in either direction in
converted to water-soluble metabolites while some the renal tubules depending on the drug
are directly eliminated without metabolism. The concentration, lipid solubility and pH. As highly
major organs of excretion are the kidneys, the lipid soluble drugs are largely reabsorbed, their
intestines, the biliary system and the lungs. Drugs excretion is slow. Acidic drugs get ionized in
are also excreted in small amounts in the saliva, alkaline urine and are easily excreted while bases
sweat and milk. are excreted faster in acidic urine. This property
Renal Excretion is useful in the treatment of poisoning. In
poisoning with acidic drugs like salicylates and
Kidney is the most important route of drug barbiturates, forced alkaline diuresis (Diuretic +
excretion. The three processes involved in the sodium bicarbonate + IV fluids) is employed to
elimination of drugs through kidneys are hasten drug excretion. Similarly, elimination of
glomerular filtration, active tubular secretion and basic drugs like quinine and amphetamine is
passive tubular reabsorption. enhanced by forced acid diuresis.
Glomerular filtration: The rate of filtration through Fecal and Biliary Excretion
the glomerulus depends on GFR, concentration
of free drug in the plasma and its molecular weight. Unabsorbed portion of the orally administered
Ionized drugs of low molecular weight (< 10,000) drugs are eliminated through the faeces. Liver
are easily filtered through the glomerular transfers acids, bases and unionized molecules
membrane. into bile by specific acid transport processes. Some
drugs may get reabsorbed in the lower portion of
Active tubular secretion: Cells of the proximal the gut and are carried back to the liver. Such
tubules actively secrete acids and bases by two recycling is called enterohepatic circulation and it
transport systems. Thus, acids like penicillin, prolongs the duration of action of the drug;
salicylic acid, probenecid, frusemide; bases like examples are chloramphenicol, tetracycline, oral
amphetamine and histamine are so excreted. contraceptives and erythromycin.
16 Pharmacology for Physiotherapy
Fig. 1.5: Plasma concentration-time curve following intravenous dose. Plasma t½ = 4 hours
Fig. 1.6: Drug accumulation and attainment of steady state concentration on oral administration
Anti-infective and Cytotoxic Action ion channels. Drugs may act on the cell membrane,
inside or outside the cell to produce their effect.
Drugs may act by specifically destroying infective
Drugs may act by one or more complex mecha-
organisms, e.g. penicillins, or by cytotoxic effect
nisms of action. Some of them are yet to be
on cancer cells, e.g. anticancer drugs.
understood. But the fundamental mechanisms of
drug action may be:
Modification of Immune Status
Vaccines and sera act by improving our immunity Through Receptors
while immunosuppressants act by depressing Drugs may act by interacting with specific
immunity, e.g. glucocorticoids. receptors in the body (see below).
allopurinol inhibits the enzyme xanthine oxidase; Agonist: An agonist is a substance that binds to
acetazolamide inhibits carbonic anhydrase. the receptor and produces a response. It has
Membrane pumps like H+ K+ ATPase, Na+ K+ affinity and intrinsic activity.
ATPase may be inhibited by drugs, e.g.
Antagonist: An antagonist is a substance that
omeprazole, digoxin.
binds to the receptor and prevents the action of
agonist on the receptor. It has affinity but no
Through Ion Channels
intrinsic activity.
Drugs may interfere with the movement of ions
Partial agonist binds to the receptor but has low
across specific channels, e.g. calcium channel
intrinsic activity.
blockers, potassium channel openers.
Ligand is a molecule which binds selectively to a
Physical Action specific receptor.
The action of a drug could result from its physical Last three decades have seen an explosion in
properties like: our knowledge of the receptors. Various receptors
Adsorption – Activated charcoal in poisoning have been identified, isolated and extensively
Mass of the drug – Bulk laxatives like psyllium, bran studied.
Osmotic property – Osmotic diuretics—Mannitol
Site: The receptors may be present in the cell
– Osmotic purgatives—Magne-
membrane, in the cytoplasm or on the nucleus.
sium sulphate
Radioactivity – 131I Nature of receptors: Receptors are proteins.
Radio-opacity – Barium sulphate contrast media.
Synthesis and life-span: Receptor proteins are
Chemical Interaction synthesized by the cells. They have a definite life
Drugs may act by chemical reaction. span after which the receptors are degraded by
Antacids – neutralise gastric acids the cell and new receptors are synthesized.
Oxidising agents – like potassium permanganate -
germicidal Functions of Receptors
Chelating agents – bind heavy metals making them The two functions of receptors are:
nontoxic. 1. Recognition and binding of the ligand
2. Propagation of the message.
Altering Metabolic Processes
For the above function, the receptor has two
Drugs like antimicrobials alter the metabolic sites (domains):
pathway in the microorganisms resulting in i. A ligand binding site—the site to bind the drug
destruction of the microorganism, e.g. molecule
sulfonamides interfere with bacterial folic acid ii. An effector site—which undergoes a change
synthesis. to propagate the message.
Drug-receptor interaction has been considered
Receptor to be similar to ‘lock and key’ relationship where
A receptor is a site on the cell with which an the drug specifically fits into the particular
agonist binds to bring about a change, e.g. receptor (lock) like a key. Interaction of the agonist
histamine receptor, α and β adrenergic receptors. with the receptor brings about changes in the
receptor which in turn conveys the signal to the
Affinity is the ability of a drug to bind to a receptor.
effector system. The final response is brought
Intrinsic activity or efficacy is the ability of a drug about by the effector system through second
to produce a response after binding to the receptor. messengers. The agonist itself is the first
General Pharmacology 21
messenger. The entire process involves a chain of response curve (DRC). Initially the extent of
events triggered by drug receptor interaction. response increases with increase in dose till the
maximum response is reached. After the
Receptor Families maximum effect has been obtained, further
increase in doses does not increase the response.
Four families (types) of cell surface receptors are
If the dose is plotted on a logarithmic scale, the
identified. The receptor families are:
curve becomes sigmoid or ‘S’ shaped (Fig. 1.7).
1. Ion channels
2. G-protein coupled receptors
Drug Potency and Maximal Efficacy
3. Enzymatic receptors
4. Nuclear receptors (receptors that regulate gene The amount of drug required to produce a
transcription). response indicates the potency. For example,
1 mg of bumetanide produces the same diuresis
Receptor Regulation as 50 mg of frusemide. Thus, bumetanide is more
potent than frusemide. In Figure 1.8, drugs A and
The number of receptors (density) and their
B are more potent than drugs C and D, drug A
sensitivity can be altered in many situations.
being the most potent and drug D—the least
Denervation or prolonged deprivation of the
potent. Hence higher doses of drugs C and D are
agonist or constant action of the antagonist all
to be administered as compared to drugs A and B.
result in an increase in the number and sensitivity
Generally potency is of little clinical significance
of the receptors. This phenomenon is called ‘up
unless very large doses of the drug needs to be
regulation.’
given due to low potency.
Prolonged use of a β adrenergic antagonist like
propranolol results in up regulation of β Maximal efficacy: Efficacy indicates the
adrenergic receptors. maximum response that can be produced by a
On the other hand, continued stimulation of drug, e.g. frusemide produces powerful diuresis,
the receptors causes desensitization and a not produced by any dose of amiloride. In Figure
decrease in the number of receptors—known as 1.8, drugs B and C are more efficacious than drugs
‘down regulation’ of the receptors. A and D. Drug A is more potent but less efficacious
than drugs B and C. Such differences in efficacy
Clinical importance of receptor regulation: After
are of great clinical importance.
prolonged administration, a receptor antagonist
should always be tapered. For example, if propra- Therapeutic index: The dose response curves
nolol—a β adrenoceptor blocker is suddenly for different actions of a drug could be different.
withdrawn after long-term use, it precipitates Thus salbutamol may have one DRC for
angina due to upregulation of β receptors. bronchodilation and another for tachycardia. The
Constant use of β adrenergic agonists in distance between beneficial effect DRC and
bronchial asthma results in reduced therapeutic unwanted effect DRC indicates the safety margin
response due to down regulation of β2 receptors. of the drug (Fig. 1.9).
Dose Response Relationship Median lethal dose (LD50) is the dose which is
lethal to 50 percent of animals of the test
The response to different doses of a drug can be population.
plotted on a graph to obtain the Dose Response
Curve. Median effective dose (ED50) is the dose that
The clinical response to the increasing dose of produces a desired effect in 50 percent of the test
the drug is defined by the shape of the dose population.
22 Pharmacology for Physiotherapy
Therapeutic index (TI) is the ratio of the • TI varies from species to species
median lethal dose to the median effective dose. • For a drug to be considered reasonably safe,
it’s TI must be > 1
LD50
Therapeutic index = ___________ • Penicillin has a high TI while lithium and
ED50 digoxin have low TI.
It gives an idea about the safety of the drug.
• The higher the therapeutic index, the safer Drug Synergism and Antagonism
is the drug When two or more drugs are given concurrently
the effect may be additive, synergistic or
antagonistic.
Additive Effect
The effect of two or more drugs get added up and
the total effect is equal to the sum of their
individual actions.
Examples are ephedrine with theophylline in
bronchial asthma; nitrous oxide and ether as
general anesthetics.
Synergism
When the action of one drug is enhanced or
facilitated by another drug, the combination is
Fig. 1.8: Dose response curves of four drugs showing synergistic. In Greek, ergon = work; syn = with.
different potencies and maximal efficacies. Drug A is Here, the total effect of the combination is greater
more potent but less efficacious than B and C. Drug D than the sum of their independent effects. It is often
is less potent and less efficacious than drugs B and C called ‘potentiation’ or ‘supra-additive’ effect.
General Pharmacology 23
Antagonism
One drug opposing or inhibiting the action of
another is antagonism. Based on the mechanisms,
antagonism can be:
• Chemical antagonism
• Physiological antagonism
• Antagonism at the receptor level
— Reversible (Competitive)
— Irreversible
• Non-competitive antagonism. Fig. 1.10: Dose response curves of an agonist: (A) in
the absence of competitive antagonist; (B) in the
Chemical antagonism: Two substances interact presence of increasing doses of a competitive
chemically to result in inactivation of the effect, antagonist
e.g. chelating agents inactivate heavy metals like
lead and mercury to form inactive complexes;
Irreversible antagonism: The antagonist binds
antacids like aluminium hydroxide neutralize
firmly by covalent bonds to the receptor. Thus it
gastric acid.
blocks the action of the agonist and the blockade
Physiological antagonism: Two drugs act at cannot be overcome by increasing the dose of the
different sites to produce opposing effects. For agonist and hence it is irreversible antagonism,
example, histamine acts on H2 receptors to e.g. adrenaline and phenoxybenzamine at alpha
produce bronchospasm and hypotension while adrenergic receptors (Fig. 1.11).
adrenaline reverses these effects by acting on
adrenergic receptors.
Insulin and glucagon have opposite effects on
the blood sugar level.
Antagonism at the receptor level: The antagonist
inhibits the binding of the agonist to the receptor.
Such antagonism may be reversible or irreversible.
Reversible or competitive antagonism: The
agonist and antagonist compete for the same
receptor. By increasing the concentration of the
agonist, the antagonism can be overcome. It is thus
reversible antagonism. Acetylcholine and atropine
compete for the muscarinic receptors. The
antagonism can be overcome by increasing the
concentration of acetylcholine at the receptor. Fig. 1.11: Dose response curves of an agonist:
d-tubocurarine and acetylcholine compete for the (A) in the absence of antagonist. (B1), (B2) and (B3) in
nicotinic receptors at the neuromuscular junction the presence of increasing doses of an irreversible
(Fig. 1.10). antagonist
24 Pharmacology for Physiotherapy
Noncompetitive antagonism: The antagonist In the elderly, the capacity of the liver and
blocks at the level of receptor-effector linkage. For kidney to handle the drug is reduced and are
example, verapamil blocks the cardiac calcium more susceptible to adverse effects. Hence
channels and inhibits the entry of Ca++ during lower doses are recommended, e.g. elderly are
depolarization. It thereby antagonises the effect at a higher risk of ototoxicity and
of cardiac stimulants like isoprenaline and nephrotoxicity by streptomycin.
adrenaline.
3. Sex: The hormonal effects and smaller body
FACTORS THAT MODIFY size may influence drug response in women.
THE EFFECTS OF DRUGS Special care is necessary while prescribing for
pregnant and lactating women and during
The same dose of a drug can produce different menstruation.
degrees of response in different patients and even
in the same patient under different situations. 4. Species and race: Response to drugs may
Various factors modify the response to a drug. vary with species and race. For example,
They are: rabbits are resistant to atropine. Then it
becomes difficult to extrapolate the results of
1. Body weight: The recommended dose is
animal experiments. Blacks need higher doses
calculated for medium built persons. For the
of atropine to produce mydriasis.
obese and underweight persons, the dose has
to be calculated individually. Though body 5. Diet and environment: Food interferes with
surface area is a better parameter for more the absorption of many drugs. For example,
accurate calculation of the dose, it is incon- tetracyclines form complexes with calcium
venient and hence not generally used. present in the food and are poorly absorbed.
Formula: Polycyclic hydrocarbons present in
cigarette smoke may induce microsomal
Body weight (kg)
Dose = _________________________ × average adult dose enzymes resulting in enhanced metabolism of
70 some drugs.
2. Age: The pharmacokinetics of many drugs
6. Route of administration: Occasionally route
change with age resulting in altered response
of administration may modify the pharmaco-
in extremes of age. In the newborn, the liver
dynamic response, e.g. magnesium sulfate
and kidneys are not fully mature to handle the
given orally is a purgative. But given IV it
drugs, e.g. chloramphenicol can produce grey
causes CNS depression and has anti-
baby syndrome. The blood-brain barrier is not
convulsant effects. Applied topically (poultice),
well-formed and drugs can easily reach the
it reduces local edema. Hypertonic magne-
brain. The gastric acidity is low, intestinal
sium sulfate retention enema reduces
motility is slow, skin is delicate and permeable
intracranial tension.
to drugs applied topically. Hence calculation
of the appropriate dose, depending on body 7. Genetic factors: Variations in an individual’s
weight is important to avoid toxicity. Also response to drugs could be genetically
pharmacodynamic differences could exist, e.g. mediated. Pharmacogenetics is concerned
barbiturates which produce sedation in adults with the genetically mediated variations in
may produce excitation in children. drug responses. The differences in response is
Formula for calculation of dose for children most commonly due to variations in the
Young’s formula amount of drug metabolizing enzymes since
Age (years) the production of these enzymes are
Child’s dose = __________________ × Adult dose
Age + 12 genetically controlled.
General Pharmacology 25
called functional tolerance. It could be due to down In fact all forms of treatment including
regulation of receptors as in opioids or due to physiotherapy and surgery have placebo effect.
compensatory mechanisms of the body, e.g. Substances used as placebo include lactose,
blunting of response to some antihypertensives some vitamins, minerals and distilled water
due to salt and water retention. injections.
Cross tolerance is the development of tolerance 12. Presence of other drugs: When two or more
to pharmacologically related drugs, i.e. to drugs drugs are used together, one of them can alter
belonging to a particular group. Thus chronic the response of the other resulting in drug
alcoholics also show tolerance to barbiturates and interactions (see Drug Interactions page 28).
general anesthetics.
ADVERSE DRUG REACTIONS
Tachyphylaxis is the rapid development of
tolerance. When some drugs are administered All drugs can produce unwanted effects. WHO
repeatedly at short intervals, tolerance develops has defined an adverse drug reaction as “any
rapidly and is known as tachyphylaxis or acute response to a drug that is noxious and unintended
tolerance, e.g. ephedrine, amphetamine, tyramine and that occurs at doses used in man for
and 5-hydroxytryptamine. This is thought to be prophylaxis, diagnosis or therapy.”
due to depletion of noradrenaline stores as the All drugs can cause adverse effects. Some
above drugs act by displacing noradrenaline from patients are more likely to develop adverse effects
the sympathetic nerve endings. Other mechanisms to drugs.
involved may be slow dissociation of the drug
from the receptor thereby blocking the receptor. 1. Side Effects
Thus ephedrine given repeatedly in bronchial Side effects are unwanted effects of a drug that are
asthma may not give the desired response. extension of pharmacological effects and are seen
with the therapeutic dose of the drug. They are
11. Psychological factor: The doctor patient predictable, common and can occur in all people,
relationship influences the response to a drug e.g. hypoglycemia due to insulin; hypokalemia
often to a large extent by acting on the patient’s following frusemide.
psychology. The patients confidence in the
doctor may itself be sufficient to relieve a 2. Toxic Effects
suffering, particularly the psychosomatic
Toxic effects are seen with higher doses of the drug
disorders. This can be substantiated by the fact
and can be serious, e.g. morphine causes
that large number of patients respond to
respiratory depression in overdosage.
placebo. Placebo is the inert dosage form with
no specific biological activity but only 3. Intolerance
resembles the actual preparation in
Drug intolerance is the inability of a person to
appearance. Placebo = ‘I shall be pleasing’ (in
tolerate a drug and is unpredictable. Patients show
Latin).
exaggerated response to even small doses of the
Placebo medicines are used in:
drug, e.g. vestibular dysfunction after a single dose
1. Clinical trials as a control
of streptomycin seen in some patients. Intolerance
2. To benefit or please a patient psycho-
could also be qualitative, e.g. idiosyncrasy and
logically when he does not actually require
allergic reactions.
an active drug as in mild psychosomatic
disorders and in chronic incurable Idiosyncrasy is a genetically determined abnormal
diseases. reaction to a drug, e.g. primaquine and
General Pharmacology 27
sulfonamides induce hemolysis in patients with antibody complexes activate the complement
G6PD deficiency; some patients show excitement system resulting in cytolysis causing thrombo-
with barbiturates. In addition, some responses like cytopenia, agranulocytosis and aplastic anemia.
chloramphenicol-induced agranulocytosis,
where no definite genetic background is known, Type III (Arthus) reactions: The antigen binds to
are also included under idiosyncrasy. In some circulating antibodies and the complexes are
cases the person may be highly sensitive even to deposited on the vessel wall where it initiates the
low doses of a drug or highly insensitive even to inflammatory response resulting in vasculitis.
high doses of the drug. Rashes, fever, arthralgia, lymphadenopathy,
serum sickness and Steven-Johnson’s syndrome
Allergic reactions to drugs are immunologically- are some of the manifestations of arthus type
mediated reactions which are not related to the reaction.
therapeutic effects of the drug. The drug or its
metabolite acts as an antigen to induce antibody Type IV (Delayed hypersensitivity) reactions
formation. Subsequent exposure to the drug may are mediated by T-lymphocytes and macro-
result in allergic reactions. The manifestations of phages. The antigen reacts with receptors on
allergy are seen mainly on the target organs viz. T-lymphocytes which produce lymphokines
skin, respiratory tract, gastrointestinal tract, blood leading to a local allergic reaction, e.g. contact
and blood vessels. dermatitis.
withdrawal syndrome are disturbing and the 8. Other Adverse Drug Reactions
person then craves for the drug, e.g. alcohol, Drugs can also damage various organ systems.
opioids and barbiturates.
Mild degree of physical dependence is seen in Organ system affected Examples
people who drink too much of coffee.
1. Hepatotoxicity Isoniazid, pyrazinamide,
paracetamol,
6. Teratogenicity chlorpromazine,
Teratogenicity is the ability of a drug to cause fetal 6-Mercaptopurine,
abnormalities when administered to the pregnant halothane, ethanol,
phenylbutazone
lady. Teratos in Greek means monster. The seda-
tive-thalidomide taken during early pregnancy for 2. Nephrotoxicity Analgesics,
aminoglycosides,
relief from morning sickness resulted in thousands
cyclosporine, cisplatin,
of babies being born with phocomelia (seal limbs).
cephelexin, penicillamine,
This thalidomide disaster (1958-61) opened the gold salts
eyes of various nations and made it mandatory to
3. Ototoxicity Aminoglycosides,
impose strict teratogenicity tests before a new drug frusemide
is approved for use.
4. Ocular toxicity Chloroquine, ethambutol
Depending on the stage of pregnancy during
5. Gastrointestinal Opioids, broad spectrum
which the teratogen is administered, it can
systems antibiotics
produce various abnormalities.
6. Cardiovascular Digoxin, doxorubicin
i. Conception — Usually resistant to
system
to 16 days teratogenic effects.
7. Respiratory system Aspirin, bleomycin,
If affected, abortion occurs.
busulfan, amiodarone,
ii. Period of — Most vulnerable period; methotrexate
organogenesis major physical
8. Musculoskeletal Corticosteroids, heparin
(17 to 55 days abnormalities occur. system
of gestation)
9. Behavioral toxicity Corticosteroids, reserpine
iii. Fetal period — Period of growth and
10. Neurological INH, haloperidol,
—56 days development—hence
system ethambutol, quinine,
onwards developmental and func- doxorubicin vincristine
tional abnormalities
11. Dermatological Doxycycline,
result. toxicity sulfonamides
Therefore, in general drugs should be avoided
12. Electrolyte Diuretics,
during pregnancy especially in the first trimester. disturbances mineralocorticoids
The type of malformation also depends on the
13. Hematological Chloramphenicol,
drug, e.g. thalidomide causes phocomelia; tetra- toxicity sulfonamides
cyclines cause deformed teeth; sodium valproate
14. Endocrine disorders Methyldopa, oral
causes spina bifida. contraceptives
When two or more drugs are given con- carbamazepine and rifampicin are enzyme
currently, the response may be greater or lesser inducers while chloramphenicol and cimetidine
than the sum of their individual effects. Such are some enzyme inhibitors.
responses may be beneficial or harmful. For
example a combination of drugs is used in Excretion: When drugs compete for the same renal
hypertension—hydralazine + propranolol for tubular transport system, they prolong each others
their beneficial interaction. But unwanted drug duration of action, e.g. penicillin and probenecid.
interactions may result in severe toxicity. Such 2. Pharmacodynamic mechanisms: Drugs acting
interactions can be avoided by adequate on the same receptors or physiological systems
knowledge of their mechanisms and by judicious result in additive, synergistic or antagonistic
use of drugs. effects. Many clinically important drug interac-
tions have this basis. Atropine opposes the effects
Site: Drug interaction can occur:
of physostigmine; naloxone antagonises
i. In vitro in the syringe before administration—
morphine; antihypertensive effects of β blockers
mixing of drugs in syringes can cause
are reduced by ephedrine or other vasoconstrictors
chemical or physical interactions—such
in cold remedies.
drug combinations are incompatible in
solution, e.g. penicillin and gentamicin
should never be mixed in the same syringe. GENE THERAPY
ii. In vivo, i.e. in the body after administration.
Gene therapy is the replacement of defective gene
Pharmacological basis of drug interactions: by the insertion of a normal, functional gene. Gene
The two major mechanisms of drug interactions transfer may be done to replace a missing or
include pharmacokinetic and pharmacodynamic defective gene or provide extra-copies of a
mechanisms. normally expressed gene. Gene therapy is aimed
at genetically correcting the defect in the affected
1. Pharmacokinetic mechanisms: Alteration in part of the body. Unlike all other drugs which
the extent or duration of response may be only alter the rate of normal cell functions, gene
produced by influencing absorption, distribution, therapy can confer new functions to the cell.
metabolism or excretion of one drug by another. Gene transfer requires the use of vectors to
deliver the DNA material, such as:
Absorption of drugs from the gut may be affected
i. Viral vectors like retroviral vectors and
by:
adenoviral vectors.
i. Binding—Tetracyclines chelate iron and
ii. Liposomes.
antacids resulting in reduced absorption
ii. Altering gastric pH Therapeutic applications of gene therapy: Gene
iii. Altering GI motility. therapy is at present a developing area. Though
originally it was seen as a remedy for inherited
Distribution: Competition for plasma protein or
single gene defects, gene therapy has now found
tissue binding results in displacement inter-
to be useful in several acquired disorders. The
actions, e.g. warfarin is displaced by
principle applications are in the treatment of
phenylbutazone from protein binding sites.
cancer, cardiovascular diseases, atherosclerosis,
Metabolism: Enzyme induction and inhibition of immunodeficiency disorders—particularly AIDS;
metabolism can both result in drug interactions anemia, Alzheimer’s disease and many infectious
(see page 14), e.g. phenytoin, phenobarbitone, diseases.
Autonomic
Nervous System
INTRODUCTION TO AUTONOMIC heart, the smooth muscles, the glands and the
PHARMACOLOGY viscera and controls the functions of these organs.
The centers for autonomic reflexes are present
The nervous system is divided (Fig. 2.1) into in the hypothalamus, medulla and spinal cord.
central and peripheral nervous systems. The Hypothalamus coordinates the autonomic
peripheral nervous system consists of autonomic activity.
and somatic nervous systems. The ANS consists of 2 major divisions—the
The autonomic nervous system (ANS) (Fig. 2.2) sympathetic and the parasympathetic (Fig. 2.3).
is not under voluntary control and therefore was Most of the viscera have both sympathetic and
so named by Langley (Autos = self, nomos = parasympathetic innervation. The two divisions
governing—in Greek). The ANS innervates the have opposing effects and normally their effects
are in a state of equilibrium. The prime function of The autonomic efferent is divided into
the sympathetic system is to help the person to sympathetic and parasympathetic divisions. The
adjust to stress and prepare the body for fight or parasympathetic efferents are carried through the
flight reactions, while the parasympathetic mainly craniosacral outflow. The sympathetic efferents
participates in tissue building reactions. Man can extend from the first thoracic to second or third
still survive without sympathetic system but not lumbar segments (T1-L3 ) of the spinal cord.
without parasympathetic. Adrenal medulla is also considered as
sympathetic ganglia and differs from the other
Autonomic innervation (Fig. 2.4): The autonomic
sympathetic ganglion in that the principal
afferents are carried in visceral nerves through
catecholamine that is released is adrenaline.
nonmyelinated fibers. For example, the para-
sympathetic afferents are carried by the 9th and Neurotransmitters: For the transmission of an
10th cranial nerves. The autonomic efferent impulse across a synapse, a neurohumoral
innervation consists of a myelinated pregang- transmitter substance is released into the synaptic
lionic fiber which synapses with the axon of a cleft. In the ANS, the neurotransmitters released
nonmyelinated postganglionic fiber. The post- are acetylcholine, noradrenaline, dopamine and
ganglionic fiber in turn forms a junction with the in adrenal medulla, it is adrenaline.
receptors of the organs supplied by it. The
junction between the pre and postganglionic fibers CHOLINERGIC SYSTEM
is called a ganglion and that between the post-
ganglionic fibers and the receptors is the Acetylcholine (ACh) an ester of choline, is an
neuroeffector junction. The traveling of an impulse important neurotransmitter of the ANS. The
along the nerve fiber is known as conduction while nerves that synthesize, store and release ACh are
its passage across a synapse is known as called ‘cholinergic.’ Acetylcholine is released in
transmission. response to cholinergic stimulation.
32
Pharmacology for Physiotherapy
ACh is released into the synaptic cleft (Fig. 2.6). TABLE 2.1: Subtypes and location
This ACh binds to and activates the choli- of cholinergic receptors
nergic receptor on the postsynaptic membrane Subtypes Location
leading to the depolarization of this membrane.
Thus the impulse is transmitted across the Muscarinic M1 Autonomic ganglia,
gastric glands, CNS
synapse.
ACh released into the synaptic cleft is rapidly M2 Heart, nerves, smooth
destroyed by the acetylcholinesterase (AChE) muscles
enzyme. Then the postsynaptic membrane is M3 Glands, smooth muscles
repolarized. M4 CNS
Cholinesterases: Acetylcholine is hydrolyzed to M5 CNS
choline and acetic acid by the enzymes
Nicotinic Nm Neuromuscular junction
cholinesterases. Two types of AChE are present:
1. True cholinesterase—at neurons, ganglia and Nn Autonomic ganglia
neuromuscular junction. Adrenal medulla, CNS
2. Pseudocholinesterase—in plasma, liver and
other organs. receptors are identified (Table 2.1). Nm receptors
Cholinergic receptors: There are two classes of are present at the skeletal muscle end plate and
cholinergic receptors—muscarinic and nicotinic. Nn receptors at the autonomic ganglia and adrenal
Muscarinic receptors are present in the heart, medulla.
smooth muscles, glands, eyes and CNS. Five
subtypes of muscarinic receptors, M1-M5 are CHOLINERGIC DRUGS
recognized (Table 2.1). Cholinergic drugs are chemicals that act at the
Nicotinic receptors are present in the same site as acetylcholine and thereby mimic its
neuromuscular junction, autonomic ganglia and actions. They are therefore called parasympatho-
adrenal medulla. Two subtypes of nicotinic mimetics or cholinomimetics.
Uses: Acetylcholine is destroyed in the gut when Glaucoma is an eye disease characterized by
given orally. On intravenous administration, it is increased intraocular pressure. If untreated,
rapidly metabolized by pseudocholinesterases in irreversible damage can occur, because optic
the plasma and by true cholinesterase at the site nerve degenerates due to constant increase in
of action. Therefore it is not used therapeutically. pressure and this leads to permanent
Among the choline esters, methacholine is rarely blindness. Glaucoma is of two types:
used. Carbachol is used in glaucoma. Bethanechol i. Acute congestive/narrow angle glau-
may be used in some cases of postoperative coma—In this, iris blocks the drainage of
paralytic ileus and urinary retention. aqueous humor at the canal of Schlemn
leading to increased intraocular pressure
CHOLINOMIMETIC ALKALOIDS (Fig. 2.7). It needs immediate treatment.
Pilocarpine is an alkaloid obtained from the leaves ii.Chronic simple/open angle glaucoma—
of Pilocarpus microphyllus. Like ACh it stimulates onset is slow; needs long-term treatment.
cholinergic receptors, but its muscarinic actions Surgery is the preferred option.
are prominent. Drugs used in glaucoma are summarized in
Its actions on the eye are important—when Table 2.3.
applied to the eye it causes miosis, spasm of 2. Pilocarpine eye drops are also used alternately
accommodation and a fall in intraocular pressure with mydriatics like homatropine to break the
(IOP). It also increases sweat (diaphoretic) and adhesions between the iris and the lens.
salivary secretions (sialogogue). 3. Pilocarpine can be used to overcome dryness
of mouth that is seen following radiation of
Adverse effects: When used as eye drops, burning
head and neck.
senzation and painful spasm of accommodation
can occur.
ANTICHOLINESTERASES
Uses Anticholinesterases (antiChEs) or cholinesterase
1. Pilocarpine is used in glaucoma (0.5-4% eye inhibitors are drugs which inhibit the
drops). Pilocarpine ocusert is a special drug enzyme cholinesterase. As their structure
delivery system that can deliver pilocarpine resembles that of ACh, they bind to AChEs and
constantly for 7 days. inactivate them.
Fig. 2.7: Schematic diagram showing pathway for the drainage of aqueous humor
Autonomic Nervous System 37
the destruction of ACh. They thus increase the 6. Cobra bite: Cobra venom, a neurotoxin causes
force of contraction and improve muscle power skeletal muscle paralysis. Specific treatment
by more frequent activation of the existing is antivenom. Intravenous edrophonium
nicotinic receptors. In advanced disease, prevents respiratory paralysis.
anticholinesterases are not effective because 7. Alzheimer’s disease: Rivastigmine and
the available nicotinic receptors are very few. donepezil are tried.
Factors like infection, surgery and stress
can result in severe muscle weakness called – Irreversible Anticholinesterases
myasthenic crisis. But severe weakness may
Organophosphorus compounds are powerful
also result from an excess dose of an inhibitors of AChE enzyme; binding with the
anticholinesterase drug (flaccid paralysis due enzyme is permanent—by covalent bonds.
to more of acetylcholine) called ‘cholinergic Actions are similar to ACh as ACh accumulates in
crisis’. These two crises can be differentiated the tissues. Organophosphates are highly lipid
by 2 mg IV edrophonium—the patient soluble and hence are absorbed from all routes
immediately improves if it is myasthenic crisis including intact skin.
but the weakness worsens if it is cholinergic
crisis. Treatment of cholinergic crisis is with Uses
atropine while myasthenic crisis requires a
Glaucoma—echothiophate eye drops are some-
higher dose of an alternative anticholinergic
times used in glaucoma.
drug.
Other drugs used in myasthenia gravis
Organophosphorus Poisoning
are—glucocorticoids—they inhibit the
production of antibodies to the nicotinic As organophosphates are used as agricultural
receptors. These are used when anti- and domestic insecticides, poisoning from
cholinesterases alone are not adequate. them is quite common. Poisoning may be
Immunosuppressants—Azathioprine and occupational—as while spraying insecticides,
cyclosporine can be used as alternatives to accidental or suicidal. Symptoms include
prednisolone in advanced myasthenia gravis. muscarinic, nicotinic and central effects; vomiting,
They inhibit the production of antinicotinic abdominal cramps, diarrhea, miosis, sweating,
receptor antibodies. increased salivary, tracheobronchial and gastric
3. Poisoning due to anticholinergic drugs: secretions and bronchospasm; hypotension,
Physostigmine is used in atropine poisoning muscular twitchings, weakness, convulsions and
and in toxicity due to other drugs with coma. Death is due to respiratory paralysis.
anticholinergic activity like phenothiazines, Treatment
tricyclic antidepressants and antihistamines. 1. If poisoning is through skin—remove clothing
4. Curare poisoning: Skeletal muscle paralysis and wash the skin with soap and water; if
caused by curare can be antagonized by consumed by oral route—gastric lavage is
AntiChEs. Edrophonium is preferred for its given.
fast action. But, neostigmine has a better 2. Maintain BP and patent airway.
capacity to antagonize the effects of curare 3. Drug of choice is atropine (2 mg IV every 10
because of which it is preferred in severe minutes till pupil dilates) because it blocks the
poisoning. muscarinic receptors and thereby antagonises
5. Postoperative paralytic ileus and urinary retention: the muscarinic effects of organophosphorus
Neostigmine may be useful. compounds.
Autonomic Nervous System 39
• Urinary disorders — Reduce urinary urgency The sympathetic postganglionic nerve fibers
and frequency. Therefore anticholinergics are that synthesize, store and release NA are called
used in urinary disorders, urologic surgeries adrenergic. Noradrenaline is stored in small
and in nocturnal enuresis in children. vesicles in the adrenergic nerve terminals. In
• Glycopyrrolate is used in preanesthetic response to nerve impulse, NA is released into
medication as it is an antisialogogue. It does the synaptic cleft by a process of exocytosis. This
not cross the blood brain barrier and therefore NA binds to adrenergic receptors located on the
has no CNS effects. postsynaptic membrane to produce the response
(Fig 2.9). A small portion of NA is metabolized by
ADRENERGIC SYSTEM the enzyme COMT. But a large portion (nearly
80%) is taken back into the nerve terminals by an
The prime function of the adrenergic or active transport process termed uptake 1, which
sympathetic nervous system is to help the human is responsible for termination of action of NA. Of
beings to adjust to stress and prepare the body for this, a fraction is metabolized by MAO and the
fight or flight reactions. When exposed to stress, remaining NA is then transferred to the storage
the heart rate and stroke volume increase with the vesicles. Some part of NA released into the
resultant increase in CO. The blood is shifted from
the skin, gut, kidney and glands to the heart,
skeletal muscles, brain and lungs, as these organs
need more blood during stress. Pupils and bronchi
are dilated and sweating is increased. Blood
glucose increases by glycogenolysis.
Neurotransmitters of the sympathetic system
are noradrenaline (NA, norepinephrine) and
dopamine (DA). Adrenaline (epinephrine) is the
major hormone secreted by the adrenal medulla.
Synthesis of catecholamines: The 3 cate-
cholamines—NA, adrenaline and DA are
synthesized from the amino acid tyrosine (Fig. 2.8). Fig. 2.8: Biosynthesis of catecholamines
synaptic cleft penetrates into the effector cells and ADRENERGIC DRUGS (Sympathomimetics)
is known as uptake 2.
Sympathomimetics are drugs whose actions
Adrenergic receptors Alquist classified mimic that of sympathetic stimulation. They may
adrenergic receptors into 2 types—α and β. With be classified in various ways.
the availability of newer, synthetic, selective
I. Chemical classification—based on
drugs, these are further classified into sub-
presence/absence of catechol nucleus
divisions. We now know α1 α2, β1, β2 and β3
1. Catecholamines Noradrenaline (NA),
adrenergic receptors.
Adrenaline,
The stimulation of α receptors mainly produces
Dopamine (DA),
excitatory effects (exception-GIT); β stimulation
Isoprenaline
causes mainly inhibitory effects (exception- heart).
(Synthetic)
The characteristics of these receptors are given in
Table 2.5. α 2 receptors are located on the 2. Non-catecholamines Ephedrine,
presynaptic membrane. When the concentration Amphetamine
of NA reaches adequate levels, these presynaptic II. Depending on the mode of action
α2 receptors are stimulated and inhibit the further 1. Directly acting by interacting with
release of NA. Thus α2 receptors exert a negative sympathomimetics adrenergic receptors
feed back on NA release. α2 receptors are also — NA, isoprenaline,
present postsynaptically in pancreatic islets, dopamine,
platelets and brain. adrenaline
2. Indirectly acting by releasing NA from rate, force of contraction, cardiac output and
sympathomimetics nerve terminals— conduction velocity. The work done and the
Amphetamine, resultant O2 consumption of the heart is increased.
Tyramine
Blood vessels and BP: Blood vessels of skin
3. Mixed action amines both direct and and mucous membrane are constricted (α1) and
indirect actions:
that of skeletal muscles are dilated (β2 ) by
Ephedrine,
adrenaline.
Methoxamine
Moderate doses given IV produce a rapid
III. Therapeutic or clinical classification increase in BP followed by a fall— a biphasic
1. Vasopressors Noradrenaline, response. The rise in BP is due to α1 mediated
Dopamine, vasoconstriction. Action on β receptors is more
Methoxamine, persistent and as the action on alpha receptors
Metaraminol wears off, the action on β receptors gets unmasked
2. Cardiac stimulants Adrenaline, resulting in ↓ BP. Sir Henry Dale demonstrated
Dopamine, that when α receptors are blocked (with alpha
Dobutamine, blockers—ergot alkaloids), adrenaline produces
Isoprenaline, only a fall in BP and this is named after him as
Ephedrine Dale’s vasomotor reversal (or Dale’s pheno-
3. CNS stimulants Amphetamine, menon).
Ephedrine Noradrenaline is mainly an alpha agonist and
4. Bronchodilators Adrenaline, brings about a rise in BP.
Isoprenaline, Other vascular beds: Adrenaline causes renal
Salbutamol, vasoconstriction resulting in fall in renal blood
Terbutaline, flow; it also causes pulmonary and mesenteric
Salmeterol vasoconstriction.
5. Nasal decongestants Ephedrine, Cerebral and coronary blood flow is enhanced.
Pseudoephedrine,
Phenyl- 2. Smooth Muscles
propanolamine, Bronchi: Adrenaline is a powerful bronchodilator
Phenylephrine, and a weak respiratory stimulant. Pulmonary
Oxymetazoline, vasoconstriction relieves bronchial congestion.
Xylometazoline All these result in an increase in vital capacity.
6. Appetite suppres- Fenfluramine, Uterus: Nonpregnant uterus—contracts
sants (anorectics) Dexfenfluramine Last month of pregnancy—relaxes.
7. Uterine relaxants Salbutamol, Gut: Smooth muscle is relaxed—but weak and
Terbutaline, transient action.
Isoxuprine, ritodrine
Splenic capsule: Contracts resulting in the release
ACTIONS of RBCs into the circulation.
Pilomotor muscles of the hair follicle: Contraction.
1. Cardiovascular System
Bladder: Detrusor is relaxed while trigonal
Heart: Adrenaline is a powerful cardiac stimulant. sphincter is contracted thereby increasing the
Acting through β1 receptors, it increases the heart holding capacity of the bladder.
44 Pharmacology for Physiotherapy
Arterioles are dilated more than veins resulting urethra reduce resistance to urine outflow.
in hypotension. There is no significant tachycardia Prazosin is useful in patients who cannot be
(as α2 receptors are spared there is no ↑ in NA operated upon.
release).
It is orally effective and is metabolized in the BETA ADRENERGIC BLOCKING AGENTS
liver.
β-blockers are drugs that block the actions of
Adverse effects—First dose phenomenon—1 hour catecholamines mediated through the β receptors.
after the initial dose, marked postural hypotension
occurs which may lead to fainting. To avoid this, Classification
prazosin should be started with a low dose and 1. Non-selective: Propranolol, nadolol, timolol,
taken at bed time. sotalol.
2. Cardioselective (β 1): Metoprolol, atenolol,
Terazosin is longer-acting and can be given once
acebutolol, esmolol.
daily.
3. Partial agonists: Pindolol, oxprenolol.
Yohimbine is a relatively selective α2-blocker 4. With additional alpha blocking property:
which increases BP and heart rate due to ↑ NA Labetalol, carvedilol.
release. It causes congestion of genitals for which
it is used to treat psychogenic impotence. It is also Pharmacological Actions
claimed to be an aphrodisiac (drug that increases 1. CVS: β-blockers decrease heart rate, force of
sexual desire) though the effect is only psycho- contraction and cardiac output. Blood
logical. pressure falls. The effect is more pronounced
in presence of increased sympathetic tone than
Uses of α-blockers in a normal situation.
1. Hypertension—Selective α 1 -blockers like AV conduction is delayed. Myocardial oxygen
prazosin are used in the treatment of hyper- requirement is reduced due to reduced cardiac
tension (page 81). Phenoxybenzamine or work.
phentolamine can be used in hypertensive High doses produce membrane-stabilizing
crisis. activity like quinidine, causing direct
2. Pheochromocytoma is an adrenal medullary depression of the heart.
tumor which secretes large amounts of 2. Exercise: β-blockers prevent the increase in
catecholamines resulting in hypertension. The heart rate and force of contraction which are
tumor has to be removed surgically. brought about by exercise. β-blockers may also
Phenoxybenzamine and phentolamine are reduce the work capacity. These effects are less
used for the preoperative management of the prominent with β1 selective agents. This is
patient and during the operation. Inoperable because blockade of β2 receptors prevents the
cases are put on long-term treatment with increase in blood flow to the skeletal muscles
phenoxybenzamine. during exercise. β-blockers improve exercise
3. Peripheral vascular diseases like Raynaud’s tolerance in patients with angina.
phenomenon may be benefited by α-blockers 3. Respiratory tract: Blockade of β2 receptors in
which afford symptomatic relief. the bronchial smooth muscle causes increase
4. Congestive cardiac failure—Because of its in airway resistance—may precipitate acute
vasodilator action, prazosin is useful in CCF. attacks in asthmatics.
But ACE inhibitors are preferred. 4. Eye: Many β-blockers reduce intraocular
5. Benign prostatic hypertrophy (BPH)—Blockade pressure by decreased secretion of aqueous
of α1 receptors in the bladder, prostate and humor.
Autonomic Nervous System 49
Fig. 3.1: d-Tc molecules bind to nicotinic receptors and prevent the binding of ACh on these receptors
ventilation and fresh blood transfusion are endotracheal intubation. SMRs are also useful
needed. in laryngoscopy, bronchoscopy, eso-
phagoscopy and in orthopedic procedures like
Adverse Reactions reduction of fractures and dislocations.
2. In electroconvulsive therapy SMRs protect the
Postoperative muscle pain is a common adverse
patient from convulsions and trauma during
effect of SCh. It may be due to the damage to muscle
ECT.
fibers that occurs during initial fasciculations.
3. In spastic disorders SMRs are used to overcome
Hyperkalemia: This may result in cardiac arrest in the spasm of tetanus, athetosis and status
patients with burns and nerve injuries. epilepticus.
Cardiac arrhythmias: SCh can cause cardiac
CENTRALLY ACTING MUSCLE RELAXANTS
arrhythmias.
These drugs act on higher centers and cause
Malignant hyperthermia: It is a rare genetically
muscle relaxation without loss of consciousness.
determined condition where there is a sudden
They also have sedative properties.
increase in body temperature and severe muscle
spasm due to release of intracellular Ca++ from
Mechanism of Action
the sarcoplasmic reticulum. Certain drugs like
halothane, isoflurane and succinylcholine can Centrally acting muscle relaxants depress the
trigger this process which can be fatal. Combi- spinal polysynaptic reflexes. These reflexes
nation of halothane and SCh is the most common maintain the muscle tone. By depressing these
triggering factor. Intravenous dantrolene is life- spinal reflexes, centrally acting SMRs reduce the
saving in malignant hyperthermia. Oxygen muscle tone.
inhalation and immediate cooling of the body also
help. Diazepam has useful antispastic activity. It can
be used in relieving muscle spasm of almost any
Drug Interactions origin including local muscle trauma (see page
107).
1. General anesthetics augment the action of
SMRs. Baclofen is an analog of the inhibitory
2. Anticholinesterases like neostigmine—reverse neurotransmitter GABA. It is a GABA agonist—it
the action of competitive blockers. depresses the monosynaptic and polysynaptic
3. Aminoglycosides and calcium channel reflexes in the spinal cord. It relieves painful
blockers potentiate the action of SMRs. spasms including flexor and extensor spasms
and may also improve bladder and bowel
Uses of Peripherally Acting functions in patients with spinal lesions. Normal
Skeletal Muscle Relaxants tendon reflexes and voluntary muscle power are
not affected. Baclofen is generally given orally.
Inappropriate use of peripherally acting SMRs
Side effects are drowsiness, weakness and
can be fatal. Hence they should be given only by
ataxia. Baclofen should be gradually withdrawn
qualified anesthetists or adequately trained
after prolonged use.
doctors.
1. Adjuvant to anesthesia Adequate muscle Mephenesin is not preferred due to its side effects.
relaxation is essential during surgeries. A number of related drugs like carisoprodol,
Skeletal muscle relaxants are used as methocarbamol, chlorzoxazone are used in acute
adjuvants to general anesthesia. Short-acting muscle spasm caused by local trauma. All of them
SMRs like succinylcholine is used during also cause sedation.
Musculoskeletal System 55
Tizanidine is a congener of clonidine. It is a central hepatotoxicity. Liver function tests should be done
α2 agonist like clonidine. It increases presynaptic to look for hepatotoxicity.
inhibition of motor neurons and reduces muscle
spasms. Adverse effects include drowsiness, Uses
weakness, hypotension and dry mouth. Dantrolene is used in spastic disorders and
Tizanidine is used in the treatment of spasticity malignant hyperthermia (page 54, 99). Dantrolene
due to stroke, multiple sclerosis and amyotropic prevents the release of Ca++ from the sarcoplasmic
lateral sclerosis. reticulum and relieves muscle spasm in malig-
nant hyperthermia.
Other centrally acting spasmolytic agents
include riluzole, gabapentin and progabide.
Riluzole has both presynaptic and postsynaptic DRUGS USED IN THE TREATMENT OF
effects. It inhibits glutamate release in the CNS. It LOCAL MUSCLE SPASM
is well tolerated with minor adverse effects like Several agents are used for the treatment of
nausea and diarrhea. It is used to reduce spasticity local muscle spasms which may result from
in amyotropic lateral sclerosis. injury or strain. Cyclobenzaprine, metaxalone,
carisoprodol, chlorzoxazone, meprobamate, and
Uses of Centrally Acting Muscle Relaxants methocarbamol are some of them. They have the
following common features:
1. Musculoskeletal disorders like muscle strains,
• All these drugs act by depressing spinal
sprains, myalgias, torticollis, cervical root
polysynaptic reflexes.
syndromes, herniated disc syndromes, low
• Common adverse reactions include
backache, dislocations, arthritis, fibrositis and
drowsiness and dizziness.
bursitis all cause painful muscle spasms.
• Cyclobenzaprine has anticholinergic effects
Muscle relaxants are used with analgesics in
and can therefore cause dryness of mouth,
these. drowsiness and dizziness.
2. Spastic neurological disorders like cerebral palsy, • Many of them are available in combination
multiple sclerosis, poliomyelitis, hemiplegia with NSAIDs.
and quadriplegia are treated with diazepam • NSAIDs are equally or more effective in
or baclofen. relieving muscle spasms.
3. Tetanus Diazepam is given IV.
4. ECT Diazepam is given along with periphe- Botulinum toxin is produced by the anerobic
rally acting SMRs. bacterium Clostridium botulinum. The toxin
5. Orthopedic procedures like fracture reduction inhibits the release of acetylcholine at the
may be done after administering diazepam. cholinergic synapses resulting in flaccid paralysis
of skeletal muscles.
Botulinum toxin is useful (local injection) in
Directly Acting Muscle Relaxants
the treatment of dystonias, including sports or
Dantrolene directly affects the skeletal muscle writer’s cramps, muscle spasms, tremors, cerebral
contractile mechanism. It inhibits the muscle palsy and in rigidity seen in extrapyramidal
contraction by preventing the calcium release from disorders. It is commonly used to relieve
the sarcoplasmic reticulum. blepharospasm. Botulinum toxin is also gaining
Adverse effects include drowsiness, dizziness, popularity in cosmetic therapy to remove facial
fatigue, muscle weakness, diarrhoea and rarely lines by local injection.
56 Pharmacology for Physiotherapy
polymyositis and dermatomyositis. The etiology active exercises should be encouraged. Training
is not known but toxins and infections may be the use of inspiratory muscles can be of benefit for
involved. Inclusion body myositis is a type of patients with inspiratory muscle weakness.
inflammatory myopathy with frequent episodes Other facilitatory measures like grip bars,
of distal muscle weakness. In biopsy of the raised toilet seats, walking aids can also be of help.
muscle, unique inclusions are seen in the muscle.
Treatment is to suppress inflammation. 2. Demyelinating Disease
Drugs used are:
Demyelinating disease could be acute inflam-
• Glucocorticoids
matory demyelinating polyneuropathy [Guillian
• Immunosuppressive agents
Barre (GB) Syndrome] or Chronic Inflammatory
• Hormone replacement therapy in postmeno-
Demyelinating disease.
pausal women
Acute demyelinating disease is a motor
• Physiotherapy.
neuropathy which develops over 1-4 weeks after
Glucocorticoids are the first line drugs because respiratory infection or diarrhea. Microorganisms
they suppress inflammation. Prednisolone is commonly involved are Campylobacter jejunum and
started in the dose of 1-2 mg/kg/day in 2-3 cytomegalovirus. Cell mediated immune response
divided doses. A gradual improvement in grip is directed at the myelin protein of the spinal roots
strength may be noticed. However, this condition and cranial nerves. This results in the release of
is slow to respond and some may take as long as inflammatory mediators viz cytokines which
3 months. Once the response is established, a block nerve conduction and complement mediated
lower maintenance dose is effective to prevent destruction of the myelin sheath and associated
axon.
steroid – induced osteoporosis. Daily dietary
Clinical features include prodromal symptoms
supplements of calcium and vitamin D should be
with headache, vomiting, fever, pain in the back
given, guided by screening of bone mineral
and limbs. After a few days, the stage of paralysis
density.
begins with distal paresthias, rapidly ascending
Immunosuppressive agents – Patients who do muscle weakness, facial and bulbar weakness,
not respond to steroids or poorly tolerate steroids (ophthalmoplegia) and in some patients weakness
may be put on immunosuppressive agents. of the respiratory muscles. Involvement of head
Azathioprine, methotrexate, mercaptopurine, and neck muscles causes dysphagia. Sensory
cyclophosphamide and cyclosporin are all found symptoms with pain, tingling and numbness of
to be effective. Immunoglobulins given intra- the limbs, tenderness in the muscles, cranial nerve
venously appear to be useful in patients not paralysis, depressed or loss of reflexes and
responding to the above measures. sometimes urinary retention are also seen.
Nerve conduction studies done in the first few
Hormone Replacement Therapy – Postmeno- days show prolonged distal motor latencies in
pausal women may need hormone replacement the limbs, prolonged F wave latencies and action
therapy (see page 191). potential amplitudes are small. Later stages show
slowing of nerve conduction which indicates
Physiotherapy plays a vital role in the treatment. demyelination.
Patients should be advised bed rest during periods By about 3 weeks, quadriparesis and respi-
of active inflammation. A daily exercise program ratory paralysis may develop. However majority
should be designed to include passive stretching. recover with minor residual neurological
This avoids muscle contractures. Reasonable symptoms.
58 Pharmacology for Physiotherapy
or a local anesthetic like lignocaine can also afford (like knee braces when knee is affected) — all these
temporary symptomatic relief. Local application help in reducing morbidity to a large extent.
of a gel of a NSAID like diclofenac or ibuprofen
Surgery – If medical line of treatment is ineffective,
gel may be helpful and safe in most patients.
surgery to remove the damaged fragments or in
Though drugs like tramadol and opioids may
some cases joint replacement may be needed.
relieve pain in severe OA, they should be avoided
for the risk of dependence. Their use must be
4. Myasthenia Gravis (See page 37)
restricted only to patients with severely painful
joints and debilitating disease. 5. Systemic Lupus Erythematosus
rate, force of contraction and thereby the cardiac sperm production and decreased fertility. Some
output increase; the respiratory rate, depth and cause gynecomastia, hepatotoxicity, an increase
thereby tidal volume increase. The blood vessels in serum cholesterol and psychological disorders.
of skeletal muscles are dilated which increases Androgens cause virilization in women.
blood supply as well as washes away the
metabolites formed. Bronchodilators Methylxanthines are broncho-
dilators (see page 156). The main compounds are
Drugs that Influence Exercise theophylline and caffeine. They are present in
coffee, tea and cocoa. Methylxanthines are CNS
Drugs like amphetamines, anabolic steroids, stimulants. They reduce fatigue, improve alertness
methylxanthines and cocaine improve exercise and physical performance. They are mild
performance while β-blockers decrease exercise psychomotor stimulants. They also bring about
tolerance. bronchodilation and cardiac stimulation which
add to their beneficial effects on exercise.
Amphetamine improves both mental and
physical performance (see page 45). It improves β-adrenergic agonists Adrenaline and selective
alertness and performance even in highly tiring β2 -agonists like salbutamol, terbutaline and
conditions. It postpones fatigue and brings about salmeterol are bronchodilators. Though their
a significant improvement in athletic performance bronchodilator effect may help better oxygenation
in sportsmen. Amphetamines are banned in during respiration, these drugs cause skeletal
sports. Amphetamine is also a drug of muscle tremors. The exact mechanism is not
dependence. known but they may act through β-receptors to
increase the discharge of muscle spindles. Clen-
Cocaine Like amphetamine, cocaine is a buterol is a β2-agonist used by sportsmen for its
psychomotor stimulant. It produces euphoria and anabolic effects.
increased motor activity. It inhibits the uptake of
catecholamines in the nerve terminals resulting Drugs that Decrease Exercise Tolerance
in increased sympathetic activity. Cocaine is a
drug of dependence and its long-term use results β-adrenergic blockers prevent the exercise induced
in various adverse effects. increase in heart rate and force of contraction. β-
blockers reduce the work capacity and impair
Anabolic steroids are androgens with selective exercise performance. The increase in blood flow
anabolic effects and lesser degree of androgenic to the skeletal muscle during exercise is reduced
effects. Anabolic steroids improve muscle strength. by β2 blockade. They also prevent the rise in blood
They are misused by athletes and are now banned glucose level brought about by catecholamines.
in them. But androgens can cause various side They may also increase airway resistance. By all
effects if used over a long-time including reduced these effects, β-blockers reduce exercise tolerance.
Drugs Acting
on the Kidney
• DIURETICS
• ANTIDIURETICS
DIURETICS AND ANTIDIURETIC DRUGS electrically neutral Na+ and Cl– transporter. This
transporter is blocked by thiazide diuretics.
Kidney, the excretory organ of our body serves
the important functions of excretion of waste
products, regulation of fluid volume and
electrolyte content of the extracellular fluid.
Collecting tubule: In the late distal tubule and loop. They inhibit the Na+, K+, 2Cl–, co-transport
collecting duct, NaCl– is actively reabsorbed, in mechanism. As a large amount of NaCl – is
exchange for K+ and H+ to maintain the ionic absorbed in this segment, they are highly
balance-regulated by aldosterone. Absorption of efficacious. Diuretic response increases with dose
water is under the control of antidiuretic hormone and higher doses can cause dehydration (high
(ADH). ceiling of effect).
Loop diuretics also enhance the excretion of
DIURETICS K+, Ca++ and Mg++ (But Ca++ is reabsorbed in the
distal tubule—hence no hypocalcemia). They
Diuretic is an agent which increases urine and increase reabsorption of uric acid in the proximal
solute excretion. tubule. They also alter renal hemodynamics to
reduce fluid and electrolyte reabsorption in the
CLASSIFICATION proximal tubule.
1. High efficacy diuretics Furosemide, Frusemide (Furosemide) is a sulfonamide
(Loop diuretics) Bumetanide, derivative. It is the most popular loop diuretic.
Piretanide, Given intravenously it acts in 2-5 minutes, while
Ethacrynic acid, following oral use, it takes 20-40 minutes;
Torsemide duration of action is 3-6 hours.
2. Moderate efficacy diuretics IV furosemide relieves pulmonary congestion
Thiazides Benzothiadiazines and reduces left ventricular filling pressure by
like Chlorothiazide, causing venodilation in congestive heart failure
Hydro- and pulmonary edema.
chlorothiazide,
Pharmacokinetics Furosemide is rapidly absorbed
Polythiazide,
orally, highly bound to plasma proteins and
Bendro-
excreted by kidneys.
flumethiazide
Thiazide related agents Chlorthalidone, Bumetanide is a sulfonamide like frusemide but
Clopamide, is 40 times more potent. Bioavailability is 80% and
Indapamide, is better tolerated.
Metolazone,
Xipamide Ethacrynic acid is more likely to cause adverse
3. Low efficacy diuretics effects and hence is not commonly used.
Potassium sparing Triamterene,
Adverse Effects of Loop Diuretics
diuretics Amiloride,
1. Hypokalemia and metabolic alkalosis is dose
Spironolactone
dependent and can be corrected by K +
Carbonic anhydrase Acetazolamide
replacement and correction of hypovolemia.
inhibitors
2. Ototoxicity Loop diuretics cause hearing loss
Osmotic diuretics Mannitol, Urea,
by a toxic effect on the hair cells in the internal
Glycerol
ear—more common with ethacrynic acid. It is
Methylxanthines Theophylline
dose-related and generally reversible.
Concurrent use of other ototoxic drugs should
High efficacy or Loop Diuretics
be avoided.
Loop diuretics act by inhibiting NaCl– reabsorp- 3. Hyperuricemia may precipitate acute attacks of
tion in the thick ascending limb of the Henle’s gout.
64 Pharmacology for Physiotherapy
CARDIAC GLYCOSIDES AND TREATMENT adequately contract and pump the blood out of
OF CARDIAC FAILURE the heart.
Cardiac action potential When a stimulus
The cardiac muscle is a specialized tissue with reaches the cardiac cell, specific ions move into
unique properties like excitability, contractility and out of the cell eliciting an action potential.
and automaticity. The myocardium has two types Such movement of ions across the cardiac cell may
of cells—the contracting cells and the conducting be divided into phases (Fig. 5.1).
cells. The contracting cells participate in the
Phase 0 is rapid depolarization of the cell
pumping action of the heart. SA node, AV node
membrane during which there is fast entry of
and His-Purkinje system comprise the
sodium ions into the cell through the sodium
conducting tissue of the heart. Parts of the
channels. This is followed by repolarization.
conducting tissue have the characteristic property
of automaticity. Automaticity is the ability of the Phase 1 is a short, initial, rapid repolarization
cell to generate electrical impulses spontaneously. due to efflux of potassium ions.
Normally the SA node acts as the pace maker. Phase 2 is a prolonged plateau phase due to slow
Excitability is the ability of the cell to undergo entry of calcium ions into the cell through the
depolarization in response to a stimulus. calcium channels. Cardiac cell differs from other
Contractility is the ability of the myocardium to cells in having this phase of action potential.
68 Pharmacology for Physiotherapy
repolarization: quinidine thus has membrane- sensitivity and idiosyncratic reactions can occur.
stabilizing activity, i.e. it inhibits the propagation Higher doses can cause cinchonism like quinine.
of the action potential.
Procainamide a derivative of the local anesthetic
Quinidine also has vagolytic and α-blocking
procaine has the advantages over quinidine that
properties. It is also a skeletal muscle relaxant.
it has weak anticholinergic properties and is not
Pharmacokinetics: Given orally quinidine is an α-blocker. It is better tolerated than quinidine.
rapidly absorbed, 90 percent bound to plasma Disopyramide has significant anticholinergic
proteins, metabolized in the liver and excreted in properties.
the urine.
Uses: Class I A drugs are useful in almost all
Adverse effects: Quinidine is not well-tolerated types of arrhythmias. They are used in atrial
due to adverse effects and may need to be stopped. fibrillation and atrial flutter and in ventricular
Quinidine itself can cause arrhythmias and heart arrhythmias. Because of the adverse effects,
block. Hence treatment should be monitored. quinidine is not preferred in arrhythmias but it
Hypotension, nausea, vomiting, diarrhea, hyper- can be used in malaria in place of quinine.
Cardiovascular System and Blood 73
suppresses automaticity, AV conduction and Drugs are used to improve the balance between
dilates the coronaries. Adenosine is the drug of oxygen supply and demand either by increasing
choice for acute termination of paroxysmal oxygen supply to the myocardium (coronary
supraventricular tachycardias (PSVT). dilation) or by reducing the oxygen demand
Adverse effects are nausea, dyspnea, flushing (reducing preload/afterload/heart rate or all of
and headache but are of short duration. these).
Nitrates also cause dilation of blood vessels leading to a fall in BP. Reflex tachycardia may
in the skin—resulting in flushing; dilatation of occur with some.
the meningeal vessels result in headache. 2. Heart: CCBs depress myocardial contractility,
Bronchial smooth muscles are also relaxed. reduce heart rate, cardiac work and
myocardial O2 consumption.
Adverse effects: Headache is common; flushing,
3. Coronary circulation: Coronary vasodilation
sweating, palpitation, weakness, postural
occurs, increasing coronary blood flow. Hence
hypotension and rashes can occur. Tolerance to
CCBs are useful in variant angina.
vascular effects develops on repeated long term
use. CCBs include:
Dihydropyridines: Nifedipine, nimodipine,
Uses nicardipine, amlodipine, felodipine, isradipine,
1. Angina: Sublingual nitroglycerine is the drug nitrendipine, nisoldipine.
of choice for acute anginal attacks. It relieves
Others: Verapamil, diltiazem.
pain in 3 minutes. If the pain is not relieved,
the dose may be repeated (up to 3 tablets in 15 Verapamil has prominent myocardiac depressant
minutes). actions. AV conduction is depressed and usually
Orally nitrates are also used for the bradycardia is seen. Hence it should not be
prophylaxis of angina. Nitroglycerine oint- combined with β-blockers. Fall in BP is mild as
ment may be applied over the chest. the vasodilator effect of verapamil is less potent.
2. Cardiac failure: Nitrates are useful due to their Adverse effects include constipation,
vasodilator property. bradycardia, heart block and hypotension. It may
3. Myocardial infarction: IV nitroglycerine is used precipitate CCF in patients with diseased heart.
by many physicians. Nifedipine a dihydropyridine, is a potent
4. Cyanide poisoning: Nitrates convert hemo- vasodilator and causes a significant fall in BP and
globin to methemoglobin which binds to evokes reflex tachycardia. Myocardiac depressant
cyanide, forming cyanmethemoglobin. It thus effect is weak. It can be given sublingually.
protects the important enzymes from binding Adverse effects are headache, flushing,
to cyanide. Amyl nitrite is preferred. Early palpitation, dizziness, fatigue, hypotension, leg
treatment is very important. cramps and ankle edema.
5. Antispasmodic: Nitrates relieve esophageal Other CCBs like amlodipine, felodipine,
spasm when taken sublingually before meals. nitrendipine and nicardipine are similar to
Nitrates also relieve biliary colic. nifedipine with some pharmacokinetic variations.
They have higher vascular selectivity. Nimodipine
Calcium Channel Blockers
selectively relaxes cerebral vasculature. Diltiazem
The depolarization of cardiac and vascular has less potent vasodilator effects but is a
smooth muscle cells depend on the entry of myocardiac depressant.
extracellular calcium into the cell through calcium
Pharmacokinetics: CCBs are well-absorbed but
channels. This calcium triggers the release of
undergo extensive first pass metabolism. They are
intracellular calcium from the sarcoplasmic
all highly plasma protein bound and are meta-
reticulum. All these calcium ions cause contrac-
bolized in the liver.
tion. Calcium channel blockers (CCB) inhibit the
entry of Ca++ by blocking the Ca++ channels. This
Uses of CCBs
results in the following actions:
1. Smooth muscle relaxation: Arteriolar dilatation 1. Ischemic heart diseases: CCBs, verapamil and
reducing peripheral vascular resistance, diltiazem are used in the treatment of stable
76 Pharmacology for Physiotherapy
angina. They are very effective in relieving the through nitric oxide to cause vasodilatation.
pain and spasm in vasospastic angina. Adverse effects are headache, flushing, dizziness
Verapamil is also useful in unstable angina. and hypotension. Nicorandil is used as an
2. Hypertension: Verapamil, nifedipine, amlodi- alternative to nitrates in the treatment of angina.
pine and diltiazem can be used. Nifedipine is It is used in the dose of 10-20 mg twice daily.
used sublingually in hypertensive crisis. Pinacidil is similar to nicorandil and is also useful
3. Arrhythmias: Verapamil is the drug of choice in hypertension. Minoxidil and diazoxide are K+
in PSVT. channel openers used in hypertension.
4. Peripheral vascular disease: Nifedipine is useful
in Raynaud’s disease due to its vasodilator Miscellaneous
effects.
5. Hypertrophic cardiomyopathy: Verapamil is Aspirin: Low dose aspirin is given for a long
used. period for its antiplatelet aggregatory property. It
6. Migraine: Verapamil can be used in the has been shown to prevent myocardial infarction
prophylaxis of migraine. in patients with angina.
7. Subarachnoid hemorrhage: Vasospasm that
Trimetazidine is a calcium channel blocker
follows subarachnoid hemorrhage is believed
claimed to have a protective effect on the ischemic
to be responsible for neurological defects. As
myocardium and to maintain left ventricular
nimodipine brings about cerebral vasodilation,
function. Trimetazidine belongs to a new class of
it is used to treat neurological deficits in
drugs that modulate the metabolism in the
patients with cerebral vasospasm.
myocardium. Trimetazidine inhibits the enzyme
8. Atherosclerosis: Dihydropyridines may slow
involved in fatty acid oxidation pathway in the
the progress of atherosclerosis.
myocardium. It also inhibits the cytotoxicity to
the myocardial cells. Trimetazidine thus protects
β-blockers the myocardium from ischemic damage. It is orally
β-blockers reduce the frequency and severity of effective and is well tolerated with occasional
attacks of exertional angina and are useful in the gastric irritation, fatigue and muscle cramps.
prevention of angina. Exercise, emotion and Trimetazidine is used as an add on drug along
similar situations increase sympathetic activity with other antianginal drugs in the treatment of
leading to increased heart-rate, force of contraction angina pectoris.
and BP, thereby increasing O2 consumption by
Ranolazine is a recently introduced trimetazidine
the heart. β-blockers prevent angina by blocking
derivative with a unique mechanism of action.
all these actions. They are used for the long-term
Ranolazine inhibits the late sodium current in the
prophylaxis of classical angina and may be
myocardium and prevents calcium overload in
combined with nitrates. β-blockers should always
the myocardium during ischemia. It thus reduces
be tapered after prolonged use. They are not useful
myocardial oxygen demand. Due to this cardio-
in variant angina.
protective properties, ranolazine is approved for
the prevention of angina as add on therapy in
Potassium Channel Openers
patients who do not respond to first line drugs.
Nicorandil is an arterial and venous dilator. Ranolazine in orally effective. It can cause
Opening of the K+ channels results in hyperpolari- weakness, postural hypotension, QT pro-
zation and therefore relaxation of the vascular longation, dizziness, headache and constipation.
smooth muscles. In addition nicorandil also acts Dose 500 mg sustained release tablets twice daily.
Cardiovascular System and Blood 77
coronary artery disease or renal failure. Hence Diuretics enhance the excretion of sodium and
hypertension needs to be treated. water resulting in:
Antihypertensives act by influencing the BP 1. ↓ Plasma volume → ↓ cardiac output → ↓ BP
regulatory systems viz the autonomic system, 2. ↓ Body sodium → relaxation of vascular
renin-angiotensin system, calcium channels or smooth muscles (due to Na+ depletion) → ↓
sodium and water balance (plasma volume).
PVR → ↓ BP.
Restriction of dietary salt intake will reduce
CLASSIFICATION
the dose of the diuretic needed. Thiazides are the
1. Diuretics first-line antihypertensives. They may be
• Thiazides Hydrochlorothiazide, chlortha- combined with a K+ sparing diuretic to avoid hypo-
lidone, etc. kalemia. Thiazides may be used in combination
• Loop diuretics Frusemide
with other antihypertensives. Loop diuretics are
• K + Sparing diuretics Spironolactone,
used only in hypertension with chronic renal
amiloride, triamterene.
2. Drugs acting on renin angiotensin system failure or congestive heart failure.
• Angiotensin converting enzyme inhibitors
Captopril, enalapril, lisinopril, ramipril. Drugs Acting on Renin Angiotensin System
• Angiotensin II receptor antagonist 1. Angiotensin Converting
Losartan, candesartan, valsartan. Enzyme (ACE) Inhibitors
• Renin inhibitor Aliskiren.
3. Sympatholytics Angiotensin II is a powerful vasoconstrictor.
• Centrally acting drugs: Clonidine, methyl- Aldosterone also raises the BP by increasing the
dopa plasma volume (Fig. 5.2). ACE inhibitors prevent
• Ganglion blockers: Trimethaphan the formation of angiotensin II and (indirectly)
• Adrenergic neuron blockers: Guanithidine, aldosterone. There is vasodilation and decrease
reserpine in PVR resulting in ↓ BP. As ACE also degrades
• Adrenergic receptor blockers: bradykinin, ACE inhibitors raise the bradykinin
— β-blockers propranolol, atenolol, etc. levels which is a potent vasodilator. This also
— α-blockers prazosin contributes to the fall in BP.
• Mixed α and β blockers Labetalol. The blood flow to the kidneys, brain and heart
4. Vasodilators increases due to selective vasodilation and thus
• Arteriolar dilators: Hydralazine, minoxidil, maintains adequate blood supply to these vital
diazoxide organs.
• Arteriolar and venular dilators: Sodium Pharmacokinetics: ACE inhibitors are generally
nitroprusside well-absorbed. Except captopril and lisinopril, all
5. Ca++ channel blockers Verapamil, nifedipine, others are prodrugs. Duration of action varies
etc. (Table 5.6).
blood disorders. Angioedema though rare can be 3. Myocardial infarction: ACE inhibitors started
severe. At the first sign of angioedema ACE within 24 hours and given for several weeks
inhibitors should be stopped. prevent the development of CCF and reduce
mortality.
Uses 2. Angiotensin II Receptor Antagonists
1. Hypertension: ACE inhibitors are useful in the Losartan is an angiotensin II receptor antagonist.
treatment of hypertension of all grades due to AT1 receptors present in vascular and myocardial
all causes. Addition of a diuretic potentiates tissue, brain, kidney and adrenal glomerular cells
their efficacy. They are presently the first line are blocked by losartan. Losartan relaxes vascular
antihypertensives. They are specially indi- smooth muscles, promotes salt and water
cated as antihypertensives in: excretion and reduces plasma volume. The
a. Patients with diabetes as ACE-I slow the advantage of AT II antagonists over ACE
development of nephropathy. inhibitors is that there is no increase in bradykinin
b. Renal diseases—ACE inhibitors slow the levels and its associated adverse effects like dry
progression. cough and angioedema.
c. Left ventricular hypertrophy—is gradually Adverse effects include hypotension and
reversed by ACE inhibitors. hyperkalemia. It is contraindicated in pregnancy
2. CCF: ACE inhibitors are the first line drugs. and lactation.
TABLE 5.6: Dose and duration of action of some commonly used ACE inhibitors
Drug Duration of action (in hrs) Daily dose in hypertension (mg)
Captopril 6-12 12.5-50 mg BD
Enalapril 24 2.5-20 mg OD
Lisinopril >24 5-40 mg OD
Ramipril 8-48 1.25-10 mg OD
80 Pharmacology for Physiotherapy
Uses: Losartan (50 mg OD) is used in the treatment norepinephrine which is an α2 agonist and acts
of hypertension in similar indications as that of like clonidine. Renin levels also fall. Left ventri-
ACE inhibitors. Others like candesertan and cular hypertrophy is reversed in about 12 weeks
valsartan can also be used. of treatment.
Adverse effects are sedation, dryness of mouth
3. Renin inhibitors: Aliskiren is a recently and nose, headache, postural hypotension, fluid
introduced direct renin inhibitor—blocks the retention and impotence.
effects of renin thereby reducing the blood
pressure. It can be used alone or with other drugs. Uses: It is used in mild to moderate hypertension
Dose 150-300 mg once daily. along with a diuretic.
Drugs Acting Centrally These drugs block both sympathetic and para-
sympathetic ganglia resulting in decreased
Clonidine is a selective α2 agonist. Stimulation of sympathetic tone and a fall in BP. But they produce
α2 receptors in the CNS (in the vasomotor center several side effects as they block both ganglia and
and hypothalamus), decreases central sympa- are not used now. Trimethaphan is the only
thetic outflow, blocks the release of noradrenaline ganglion blocker used intravenously to produce
from the nerve terminals leading to a fall in BP controlled hypotension during certain surgeries
and bradycardia. for its rapid and short action (15 minutes).
Adverse effects include drowsiness, dryness
of mouth, nose and eyes; parotid gland swelling Adrenergic Neuron Blockers
and pain, fluid retention, constipation and
impotence. Sudden withdrawal of clonidine will Guanethidine depletes the stores of noradrena-
lead to rebound hypertension, headache, tremors, line in the adrenergic neurons and also blocks its
sweating and tachycardia. Hence the dose should release. Because of the adverse effects like postural
be tapered. hypotension, diarrhea and sexual dysfunction, it
is not used.
Uses: Mild to moderate hypertension.
Reserpine is an alkaloid obtained from Rauwolfia
serpentina (Sarpagandhi) that grows in India. In
Other Uses
the neurons, it binds to the vesicles that store
1. In opioid withdrawal: Most withdrawal monoamines like noradrenaline, dopamine and
symptoms in opioid addicts are due to 5-HT and destroys these vesicles. It thus depletes
sympathetic overactivity and can be benefited the stores of these monoamines. Reserpine also
by treatment with clonidine. causes various side effects like drowsiness,
2. Diabetic neuropathy: Clonidine controls depression, parkinsonism, postural hypotension,
diarrhea by improving absorption of NaCl and edema and sexual dysfunction. Hence it is
water in the gut by stimulation of α2 receptors generally not preferred.
in the intestines.
3. With anesthetics: Clonidine given preoperatively Adrenergic Receptor Blockers
reduces the dose of the general anesthetic
needed due to its analgesic effects. β-blockers (see Chapter 2) are mild antihyper-
tensives. They reduce the BP due to a fall in the
α-methyl dopa—an analog of dopa, is a prodrug. cardiac output. They also lower plasma renin
It is metabolized in the body to α-methyl activity and have an additional central
Cardiovascular System and Blood 81
α and β -blockers Labetalol blocks α1 and β Uses: Hydralazine is used with a β-blocker and/
receptors. It is used intravenously in the treatment or a diuretic in moderate to severe hypertension
of hypertension in pheochromocytoma and in not controlled by the first line drugs. It can be given
hypertensive emergencies. in hypertension in pregnancy.
TABLE 5.7: Dose and route of administration of some commonly used antihypertensives
Antihypertensives Daily doses Routes
Hydrochlorothiazide + 12.5-25 mg + Oral
Amiloride 1.25-2.5 mg daily
Clonidine 100-300 μg Oral
Methyldopa 250-500 mg q 6-12 hr Oral
Atenolol 25-100 mg OD Oral
Prazosin 2-20 mg daily Oral
Hydralazine 25-50 mg q 8-24 hr Oral
Diazoxide 50-100 mg every 5-10 min IV
Sodium nitroprusside 0.2-0.3 mg/min IV
Nifedipine 10 mg SL
5-20 mg q 8-12 hr Oral
Losartan 50 mg OD Oral
For ACE inhibitors see Table 5.6
82 Pharmacology for Physiotherapy
Minoxidil is a directly acting arteriolar dilator the arterioles resulting in reduced peripheral
used in severe hypertension not responding to vascular resistance. Nifedipine produces some
other drugs. It acts by opening K+ channels in reflex tachycardia while this is not seen with
smooth muscles. verapamil and diltiazem as they are cardiac
Minoxidil stimulates the growth of hair on depressants. Fluid retention is negligible unlike
prolonged use. Hence it is used topically (2% other arteriolar dilators.
solution) in alopecia. Young men with relative • CCBs are well-tolerated, and effective.
alopecia are more likely to respond. • Sublingual nifedipine used in hypertensive
emergencies effectively lowers BP in 10
Diazoxide is related to thiazide diuretics and is a minutes.
potent arteriolar dilator. It’s mechanism of action • CCBs are of special value in patients who also
is like minoxidil. It is used in hypertensive have angina.
emergencies where monitoring of infusion is not • Sustained release preparations or long acting
possible. Diazoxide has a long duration of action CCBs may be used for smoother control of BP.
(24 hours) and is suitable in such situations. • CCBs may be used in combination with other
antihypertensives in moderate to severe
Sodium nitroprusside is a rapidly acting
hypertension.
vasodilator and it relaxes both arterioles and
venules. Both peripheral resistance and cardiac Drug Interactions of Antihypertensives
output are reduced resulting in lower myocardial
oxygen consumption. Nitroprusside acts through 1. Sympathomimetics and tricyclic anti-
the release of nitric oxide which relaxes the depressants can antagonize the effects of
vascular smooth muscles. On IV administration, sympatholytics.
it is rapid (acts within 30 seconds) and short- 2. Antihistamines add to sedation produced by
acting (duration 3 minutes) allowing titration of clonidine and methyldopa.
the dose. This makes it suitable for use in hyper- 3. NSAIDs tend to cause salt and water retention
tensive emergencies with close monitoring. It and may blunt the effect of antihypertensives.
decomposes on exposure to light; the infusion
bottle and tubing should be covered with opaque Treatment of Hypertension
foil. Mild hypertension: Treatment is started with low
dose of a single drug—a thiazide diuretic or a β-
Adverse reactions are palpitation, sweating,
blocker. If the patient does not adequately respond
weakness, nausea, vomiting and in high doses
in 3-4 weeks, an ACE inhibitor or a calcium chan-
thiocyanate toxicity including psychosis.
nel blocker should be tried. If BP is not controlled
Uses by one drug, another should be added.
1. Nitroprusside is the drug of choice in hyper- Moderate hypertension: A combination of a
tensive emergencies. diuretic with a sympatholytic may be given. If
2. It is used in situations where short-term response is inadequate add a third drug.
reduction of myocardial workload is required Severe hypertension may be associated with
as in myocardial infarction. cardiac or renal disorder. A vasodilator with a
diuretic and a β-blocker is useful.
Calcium Channel Blockers
Hypertensive emergencies: Conditions like
Calcium channel blockers (CCBs) are another hypertensive encephalopathy and acute cardiac
important group of antihypertensives. They dilate failure due to hypertension require immediate
Cardiovascular System and Blood 83
the brain which if continues for more than a few oral anticoagulants. However it carries the risk
minutes results in infarction of the brain tissue. of hemorrhage and the benefits have not been
Stroke results from focal ischemia of a part of the proved. Therefore routine heparin use is not
brain, or intracranial hemorrhage. Ischemia could recommended.
be due to a thrombus or embolus occluding a 4. Maintenance of airway, circulation and blood
blood vessel in the brain. Stroke is the commonest pressure are important in acute stroke, risk
cause of severe physical disability and about 50 factors if any like hypertension, uncontrolled
percent of patients who survive acute stroke suffer diabetes mellitus, hyperlipidemia should be
from physical disability. taken care of.
Risk factors include prolonged hypertension, 5. Rehabilitation includes physiotherapy,
diabetes mellitus, old age, heredity, hyper- speech therapy and if needed occupational
lipidemia, atherosclerosis and smoking. therapy.
Manifestations of stroke include hemiplegia 6. To reduce the risk of recurrence antiplatelet
which may be associated with signs of focal drugs should be continued for long-term.
cerebral dysfunction like aphasia, sensory loss Carotid angioplasty and stenting also prevent
and visual field defects. Transient ischemic attack restenosis.
is stroke which resolves in 24 hours. The cause
should be detected and efforts should be made to DRUGS USED IN TREATMENT OF
prevent its recurrence. PERIPHERAL VASCULAR DISEASES
Treatment of Ischemic Stroke Peripheral vascular diseases (PVD) result from
1. Thrombolytics—Though thrombolytics seem reduced blood supply to the lower limbs.
to be helpful in dissolving the clot and Reduction in blood supply may be due to organic
restoring the blood supply, it carries the risk occlusion (e.g. thrombus) or vasospasm.
of hemorrhagic transformation of the infarct Obstruction to the blood flow in the peripheral
which could be fatal. However, thrombolysis circulation due to any cause can result in ischemia
carried out within 3 hours of onset of stroke in of the area distal to it with its related consequences.
selected patients after ruling out hemorrhage Peripheral vascular diseases include
results in improvement. Intravenous infusion thromboangitis obliterans (TAO, Buerger’s
of recombinant tissue plasmogen activator is disease), Raynaud’s Phenomenon, frost bite,
started. Blood supply may also be restored by vascular complications of diabetes mellitus like
alternative methods like intra-arterial gangrene, leg and foot ulcers.
thrombolysis, mechanical dissolution or Drugs used in peripheral vascular diseases
removal of the clot. include:
2. Antiplatelet drugs—Low dose aspirin (300 1. Vasodilators
mg) should be started immediately if tPA is a. CCBs – nifedipine
not given. If thrombolytics are given, aspirin b. Adrenergic blockers – prazosin, tolazoline
may be started on the second day and should c. β adrenergic agonists – isosxuprine
be continued – alternatively, clopidogrel or 2. Anticoagulants and antiplatelet drugs –
ticlopidine can be used. Heparin, warfarin, aspirin, clopidogrel.
3. Anticoagulants—After ruling out hemorrhage 3. Other drugs:
by MRI, heparin is started intravenously to Hypolipidemics (Statins), pentoxiphylline,
prevent recurrence. Heparin is given for a week naftidofuryl oxalate, cilostazol, cyclandelate,
and then anticoagulation is continued with xanthinol nicotinate.
86 Pharmacology for Physiotherapy
Vasodilators are of no significant value in Dose: 400 mg 2-3 times a day with food.
obstructive peripheral vascular diseases because
Naftidofuryl oxalate is found to be useful in
they do not enhance the blood flow to the ischemic
peripheral vascular diseases like TAO and in
areas. Infact they may even harm such an area
cerebrovascular disorders. Though not a
because general vasodilation may shift the blood
vasodilator, it is said to improve the supply of
to other nonischemic areas described as ‘steal’
ATP to the skeletal muscles and reduce their lactate
syndrome. However, vasodilators may be used
levels—it is called a ‘metabolic enhancer’—thus
in vasospastic diseases like Raynaud’s
it improves performance in patients with TAO or
phenomenon. The strategy is to bring about
intermittent claudication where it increases the
dilation of the arterioles to allow better blood flow
walking distance. Naftidofuryl oxalate also blocks
to the limbs with minimum hypotension.
5HT 2 receptors and inhibits 5HT induced
• Calcium channel blockers – like nifedipine (See
vasoconstriction and platelet aggregation.
page 75) are good vasodilators and are
However, it is found to increase the blood flow
beneficial in patients with peripheral vascular
to the skin rather than the muscles. It has
diseases. Nifedipine is given in the dose 5 – 20
beneficial effects in the treatment of venous leg
mg thrice daily.
ulcers. Dose: 100 mg BD - TDS oral.
• Alpha adrenergic blockers – like prazosin (See
page 47) may be used in the dose of 0.5 mg Xanthinol nicotinate – both xanthine and
twice daily. nicotinic acid are vasodilators and xanthinol
• Beta adrenergic agonists like isosuxprine also nicotinate increases blood flow in several vascular
help to relieve symptoms. beds. Therefore it has been tried in cerebrovascular
insufficiency and peripheral vascular diseases.
Anticoagulants and antiplatelet drugs like
However clinically it is not proved to be useful.
heparin and warfarin prevent the formation of
clot. They are of value particularly in obstructive Dose: 300-600 mg TDS oral/300 mg IM/slow IV.
peripheral vascular disease. Aspirin 75 – 150 mg
Cilostazol is a phosphodiestrase III inhibitor. It
once a day or clopidogrel 10 mg twice daily may
has vasodilator and antiplatelet effects – improves
be used for this purpose.
pain free walking and maximum walking
Pentoxiphylline an analog of xanthine is a distance. It is used in the dose of 100 mg BD to be
phosphodiesterase inhibitor. It reduces the taken 30 minutes before breakfast and dinner. It
viscosity of the blood and enhances blood flow to can cause headache, diarrhea, dizziness and
the ischemic areas. It is also claimed to improve tachycardia and is contraindicated in heart
the flexibility of the RBCs – (called hemorrheo- failure.
logical action) resulting in an improvement of
Thromboangitis obliterans: Atheroma of the
microcirculation and is devoid of steal pheno-
peripheral arteries results in reduced blood supply
menon. It potentiates the action of anticoagulants.
to the concerned part—usually lower limbs.
Uses: Pentoxiphylline is used in transient Historically, localized inflammatory changes can
ischemic attacks, nonhemorrhagic stroke, chronic be seen in the walls of the arteries and veins
cerebrovascular insufficiency, trophic leg ulcers, leading to thrombosis. Initially there is pain in
gangrene, intermittent claudication (which could the legs on walking (intermittent claudication) but
be due to diabetes, atherosclerosis or inflammatory later pain even at rest while in severe cases there
vascular disease). Pentoxiphylline is also used in could be gangrene of the feet and legs.
AIDS patients with increased TNF (because The goal is to prevent pain, arrest progression
pentoxiphylline can inhibit the production of of the disease and decrease the risk of cardio-
TNFα) and to improve sperm motility. vascular and cerebrovascular events. Patients
Cardiovascular System and Blood 87
Heparin was discovered by McLean, a medical treatment of deep vein thrombosis and pulmonary
student in 1916. It was named ‘heparin’ as it was embolism.
first extracted from the liver. It is found in the mast
Direct thrombin inhibitors like argatroban have
cells of the liver, lungs and intestinal mucosa.
a rapid onset of action and predictable absorption;
Heparin is the strongest acid in the body.
frequent monitoring of anticoagulant therapy
Actions: Heparin is a powerful anticoagulant is not needed. Hence they are the preferred
that acts instantaneously both in vivo and in vitro. anticoagulants in several conditions.
Mechanism of action: Heparin activates plasma Synthetic heparin derivative fondaparinux is
antithrombin III which binds to the clotting factors longer acting, risk of thrombocytopenia is less and
and inactivates them. Clotting time is prolonged. does not require frequent monitoring.
Pharmacokinetics: Heparin is not effective Heparin antagonist Protamine sulphate is a
orally. It is given IV or SC. Treatment is monitored protein obtained from the sperm of certain fish.
by the clotting time. Heparin is metabolized by Given intravenously, it neutralizes heparin and
heparinase in the liver. acts as heparin antagonist in heparin overdosage.
Adverse reactions
ORAL ANTICOAGULANTS
1. Bleeding is the most common, major adverse
effect of heparin. Careful monitoring and dose Bishydroxycoumarin was the first oral anti-
control will prevent this to a great extent. coagulant to be identified in North America. Many
2. Hypersensitivity reactions—for commercial use related compounds were then developed and are
heparin is obtained from bovine lung or also being used as rat poisons.
porcine intestine. Because of its animal origin
Mechanism of action: Oral anticoagulants
allergic reactions are quite common.
prevent the synthesis of vitamin K dependent
3. Thrombocytopenia—Heparin induced platelet
clotting factors (factors II, III, IX and X) in the liver.
aggregation and formation of anti-platelet
The onset of action is slow; it develops over
antibodies can both result in thrombocyto-
1-3 days because oral anticoagulants do not
penia. Hepain should be stopped immediately
destroy the already circulating clotting factors.
at the first sign of thrombocytopenia.
Prothrombin time (PT) is measured to monitor the
4. Alopecia is reversible.
treatment. It takes 5-7 days for PT to return to
5. Osteoporosis—on long-term use.
normal after stopping oral anticoagulants.
Contraindications to Heparin Therapy Pharmacokinetics: Warfarin is completely
Bleeding disorders, thrombocytopenia, hemo- absorbed orally and is 99 percent bound to plasma
philia, severe hypertension, intracranial proteins.
hemorrhage, cirrhosis, ulcers in the gut, renal Adverse effects
failure and neurosurgery. 1. Hemorrhage is the main adverse effect.
Low molecular weight (LMW) heparins e.g., Bleeding in the intestines, brain, nose and
Enoxaparin and dalteparin are LMW heparins gums can occur.
which have longer action, lower risk of Treatment—depends on the severity:
thrombocytopenia as well as lower risk of bleeding a. Stop the anticoagulant.
when compared to standard heparin prepa- b. Fresh blood transfusion is given to supply
rations. They are used for the prevention and the clotting factors.
Cardiovascular System and Blood 91
and the effect lasts for 7 to 10 days-till fresh Eptifibatide and tirofiban are peptides given
platelets are formed. Aspirin is the most as IV infusion. They are short acting and are tried
commonly used antiplatelet drug. in unstable angina and myocardial infarction.
Dipyridamole is a phosphodiesterase inhibitor
Others
which interferes with platelet function by
increasing platelet cyclic AMP levels. It is used Epoprostenol (PGI2) can be used during hemo-
along with aspirin for the prophylaxis of dialysis to prevent platelet aggregation as an
thromboemboli in patients with prosthetic heart alternative to heparin.
valves.
Uses of Antiplatelet Drugs
ADP Antagonists 1. Myocardial infarction—Aspirin with
Ticlopidine ADP binds to receptors on platelets thrombolytics improve survival in acute MI.
to bring about platelet aggregation. Ticlopidine is Long-term treatment with aspirin reduces
a prodrug. Its active metabolite blocks ADP reinfarction in post-MI patients.
receptors and prevents platelet aggregation. Onset 2. Unstable angina and stable angina pectoris-
of action is slow (7-11 days) and the antiplatelet Aspirin reduces the risk of acute MI.
effect remains for some days even after stopping Clopidogrel may be added to aspirin in
the drug. Dose — 250 mg twice daily. unstable angina.
Adverse effects include dyspepsia, diarrhea, 3. In patients with prosthetic heart valves,
bleeding and leukopenia. It is used in patients valvular heart disease, coronary artery bypass
who cannot tolerate aspirin. surgery–long-term use of low dose aspirin is
recommended.
Clopidogrel has structural similarity to 4. Cerebral thrombosis and TIA—In patients
ticlopidine with similar mechanism of action. Like with transient ischemic attacks aspirin
ticlopidine it is a prodrug and the active metabolite reduces the incidence of stroke and mortality.
blocks ADP receptors. Its actions are additive with In cerebral thrombosis aspirin prevents
aspirin as the mechanisms are different. Toxicity recurrence.
is milder with lesser incidence of leukopenia and 5. Atrial fibrillation—If oral anticoagulants can
thrombocytopenia. not be given, aspirin is useful.
Clopidogrel is used as an alternative when
aspirin cannot be used. It can also be used with COAGULANTS
aspirin for additive effects.
Coagulants are drugs that promote coagulation
Glycoprotein IIb/IIIa receptor antagonists (procoagulants) and control bleeding. They are
Fibrinogen and Von Willebrand afactor bind to also called hemostatics. They may be used locally
glycoprotein IIb/IIIA receptors on the platelets and or systemically. Local hemostatics are called
mediate the action of platelet agonists like styptics. Physical methods like application of
thrombin, collagen and TXA2. Drugs that block pressure, tourniquet or ice can control bleeding.
these receptors inhibit platelet aggregation
Styptics are local hemostatics that are used on
induced by all platelet agonists.
bleeding sites like tooth socket. They are:
Abciximab is a monoclonal antibody which binds 1. Adrenaline: Sterile cotton soaked in 1:10,000
glycoprotein IIb/IIIA receptors and inhibits solution of adrenaline is commonly used in
platelet aggregation. It can cause bleeding and tooth sockets and as nasal packs for epistaxis.
allergic reactions. It is used in patients undergoing Adrenaline arrests bleeding by vasoconstric-
coronary angioplasty. tion.
94 Pharmacology for Physiotherapy
Vitamin K
Dietary sources of iron: Food that is rich in iron
Vitamin K is a fat-soluble vitamin essential for the are liver, egg yolk, meat, fish, chicken, spinach,
biosynthesis of clotting factors (factors II, VII, IX dry fruits, wheat and apple.
and X by the liver).
Absorption: The average Indian diet provides
about 10-20 mg of iron. Ten percent of this iron is
Uses absorbed. It is mostly absorbed from the upper
1. Vitamin K deficiency. gut in the ferrous form. During deficiency,
2. Newborn babies lack intestinal flora and have absorption is better.
low levels of prothrombin and other clotting Factors that influence iron absorption
factors. Routine administration of vitamin K—
Ascorbic Antacids,
1 mg IM prevents hemorrhagic disease of the acid, amino phosphates,
newborn. acids, meat, Increase phytates, Decrease
3. Oral anticoagulant toxicity. ↑gastric absorption tetracyclines, absorption
acidity presence of
Other Coagulants food in the
stomach
Fresh plasma or whole blood is useful in most
coagulation disorders as it contains all the clotting Transport and distribution: Iron is transported
factors. Other concentrated plasma fractions like with the help of a glycoprotein transferrin and
fibrinogen, factors VIII, II, VII, IX and X are stored as ferritin and hemosiderin, in liver, spleen
available for the treatment of specific deficiencies. and bone marrow.
Snake venoms: Some venoms like Russels viper
Preparations of Iron
venom stimulate thrombokinase and promote
coagulation. Iron can be given both orally and parenterally.
Cardiovascular System and Blood 95
• GENERAL ANESTHETICS
• LOCAL ANESTHETICS
• SEDATIVE HYPNOTICS
• ALCOHOLS
• ANTIEPILEPTICS
• DRUGS USED IN PARKINSONISM
• OPIOID ANALGESICS AND ANTAGONISTS
• NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
• DRUGS USED IN RHEUMATOID ARTHRITIS AND GOUT
• DRUGS USED IN PSYCHIATRIC DISORDERS—ANTIPSYCHOTICS, ANTIDEPRESSANTS
AND ANTIANXIETY AGENTS
• ANTIDEPRESSANTS
• CNS STIMULANTS
Amnesia lasts for 1-2 hr. Premedication with symptoms may be seen—due to droperidol. It is
atropine is needed. Return to consciousness is employed for endoscopies, burn dressing,
gradual. Delirium may be accompanied. If angiographies and other diagnostic and minor
diazepam is administered pre and postopera- surgical procedures.
tively, delirium can be avoided. Heart rate, CO
Neuroleptanesthesia : Addition of 65 percent N2O
and BP are increased due to sympathetic stimu-
+ 35 percent O2 to the above combination produces
lation.
neuroleptanesthesia.
Advantages
• Provides profound analgesia and can be used BENZODIAZEPINES
as a single agent for minor procedures.
Benzodiazepines like diazepam, lorazepam and
• Respiration is not depressed, does not induce
midazolam are used to induce or supplement
hypotension.
anesthesia. They cause sedation, amnesia and
• Less likely to induce vomiting.
reduce anxiety which are beneficial in such
• Pharyngeal and laryngeal reflexes are only
patients. BZD may be employed alone in pro-
slightly affected.
cedures like endoscopies, reduction of fractures,
• It is particularly useful in children and poor-
cardiac catheterization and cardioversion. IV
risk patients and also in asthmatic patients
midazolam is particularly preferred as it is faster
since it does not induce bronchospasm.
and shorter-acting, more potent and does not cause
Disadvantages pain or irritation at the injection sites. BZDs are
• Hallucinations and involuntary movements also used as preanesthetic medication.
may occur during recovery.
• May be dangerous in hypertensives as it raises PREANESTHETIC MEDICATION
the BP.
Prior to anesthesia, certain drugs are administered
Contraindications: Hypertension, CCF, cerebral in order to make anesthesia safer and more
hemorrhage, increased intracranial tension, pleasant and is known as preanesthetic medi-
psychiatric disorders and pregnancy before term. cation. It is given in order to:
1. Decrease anxiety.
NEUROLEPTANALGESIA 2. Provide amnesia for the preoperative period.
3. Relieve preoperative pain if present.
A combination of fentanyl and droperidol is used.
4. Make anesthesia safer.
Fentanyl is a short-acting (30-50 min) and potent 5. Reduce side effects of anesthetics.
opioid analgesic (page 124). 6. Reduce gastric acidity.
To achieve the above purpose, more than one
Droperidol is a rapidly acting, potent neuroleptic
drug is required. An informative, supportive,
related to haloperidol.
preoperative visit by the anesthesiologist is very
When the combination is given IV, a state of
much essential.
‘neuroleptanalgesia’ is produced. This is charac-
terized by calmness, psychic indifference and Sedative hypnotics: Antianxiety agents like
intense analgesia without loss of consciousness. benzodiazepines are used extensively as
It lasts for 30-40 min. Fentanyl 0.05 mg + preanesthetic medication. They reduce anxiety
droperidol 2.5 mg/ml—4 to 6 ml is infused IV and produce sedation. Diazepam 5-10 mg is given
over 10 min. Patient is drowsy but cooperative. orally. It also produces amnesia. Barbiturates are
Respiratory depression is present. There is a slight not preferred due to the disadvantages like
fall in BP and HR. During recovery extrapyramidal respiratory depression.
Central Nervous System 101
Antihistamines have sedative, antiemetic and postoperative constipation and urinary retention;
anticholinergic properties and are useful, e.g. precipitate asthma and delay recovery from
promethazine. anesthesia.
Antiemetics: Metoclopramide, domperidone or Balanced anesthesia: Since it is not possible to
ondansetron may be used. Antihistamines with achieve ideal anesthesia with a single drug,
antiemetic properties may also be used for this multiple drugs are employed—preanesthetic
purpose. medication, IV anesthetics for induction,
inhalational agents for maintenance, oxygen,
Anticholinergic drugs: Some irritant anesthetics skeletal muscle relaxants and analgesics to attain
like ether increase the salivary and respiratory balanced anesthesia.
secretions. The secretions from the oral cavity may
enter into the larynx causing various problems LOCAL ANESTHETICS
including laryngospasm and aspiration
pneumonia. Hence we need drugs that reduce Local anesthetics (LAs) are drugs that block nerve
these secretions. But we now have less irritant conduction when applied locally to nerve tissue
anesthetics and secretions are less of a problem. in appropriate concentrations. Their action is
Atropine, scopolamine or glycopyrrolate can be completely reversible. They act on every type of
used. They nerve fiber and can cause both sensory and motor
• Reduce the secretions. paralysis in the innervated area. They act on
• Prevent bradycardia due to vagal stimulation. axons, cell body, dendrites, synapses and other
• Prevent laryngospasm which is due to excitable membranes that utilize sodium channels
excessive secretions. as the primary means of action potential genera-
Scopolamine produces more sedation. Glyco- tion.
pyrrolate is a derivative of atropine. As compared Cocaine was the first agent to be isolated by
to atropine glycopyrrolate is longer acting, and is Niemann in 1860. Inspite of its addiction poten-
less likely to cause significant tachycardia. It also tial, cocaine was used for 30 years as a surface
produces less sedation than scopolamine. anesthetic. In an effort made to improve the
properties of cocaine, procaine was synthesized
Drugs that reduce acidity: H 2 blockers like in 1905. It ruled the field for the next 50 years. In
ranitidine decrease gastric acid secretion and are 1943, lignocaine was synthesized and it con-
given on the night before surgery. Decrease in tinues to dominate the field of local anesthetics
gastric secretions reduces the damage to lungs if till today.
aspiration occurs when the patient is on Classification of local anesthetics (LAs) based
anesthesia. on the route of administration and duration of
action—
Gastrokinetic agents: Metoclopramide is a
dopamine antagonist that promotes gastro- I. Injectable
intestinal motility and increases the tone of 1. Short-acting — Procaine,
esophageal end of the stomach. This speeds up chloroprocaine
gastric emptying. The combination of an H2 2. Intermediate-acting — Lignocaine, prilocaine
blocker + metoclopramide provides best protection 3. Long-acting — Tetracaine
against aspiration. (amethocaine),
bupivacaine
Opioids: Like morphine and pethidine reduce — Dibucaine
anxiety and apprehension, provide analgesia and (cinchocaine),
reduce the dose of the anesthetic required. But they ropivacaine,
depress respiration and may cause hypotension, etidocaine.
102 Pharmacology for Physiotherapy
II. Surface — Lignocaine, cocaine, 2. Reduces systemic toxicity of LAs since the
anesthetics tetracaine, benzocaine, absorption rate is reduced and as it gets
oxethazaine, absorbed, it gets metabolized.
dibucaine, dyclonine
SYSTEMIC ACTIONS
Depending on the linking chain in their
structure, LAs can be classified as: Depending on the concentration attained in the
Ester linked – Cocaine, procaine, tetracaine, plasma, any LA can produce systemic effects. LAs
benzocaine, chloroprocaine interfere with the function of all organs in which
Amide linked – Lignocaine (lidocaine), conduction or transmission of impulses occur.
mepivacaine, bupivacaine, Thus CNS, autonomic ganglia, NMJ and all
etidocaine, prilocaine and muscles are affected.
ropivacaine.
CNS: Local anesthetics depress the inhibition from
MECHANISM OF ACTION the cerebral cortex. This loss of inhibition results
in unopposed excitatory activity which is
Local anesthetics prevent the generation and the manifested as restlessness, tremors and may
conduction of nerve impulses. The primary proceed to convulsions. This central stimulation
mechanism of action is blockade of voltage-gated is followed by generalized CNS depression and
sodium channels. death may result from respiratory failure.
Local anesthetics directly interact with specific
sites on the voltage-sensitive Na+ channels and CVS: The primary site of action is the myo-
gradually raise the threshold for excitation. With cardium—lignocaine decreases excitability,
increasing concentration, impulse conduction conduction rate and force of contraction (quinidine
slows, rate of rise of action potential (AP) declines, like effects). It also causes arteriolar dilatation.
AP amplitude decreases and finally the ability to Since procaine is short-acting, procainamide is
generate an AP is abolished. These result from used as an antiarrhythmic. Bupivacaine is more
binding of LA to more and more sodium channels. cardiotoxic than other LAs.
Thus, it prevents the generation of an AP and its
Smooth muscle: LAs depress contractions in the
conduction.
intact bowel. They alsededemascular and
Small nerve fibers are more susceptible as they
bronchial smooth muscles.
present a greater surface area per unit volume.
Thus, smaller fibers are blocked first—autonomic
PHARMACOKINETICS
fibers are blocked first followed by sensory fibers
conducting pain, temperature sense, then touch, Local anesthetics are rapidly absorbed from the
pressure and vibration sensations in the same mucous membranes and abraded skin. Rate of
order. Sensory and motor fibers are equally absorption is dependent on the vascularity of the
sensitive. Non-myelinated fibers are blocked more area. Thus, vasoconstriction decreases the
readily than the myelinated when they are of absorption. Toxicity depends on the balance
smaller diameter. between absorption and metabolism, i.e. if it gets
Addition of a vasoconstrictor like adrenaline metabolized as it gets absorbed, then toxicity is
(1:1,00,000 to 1: 2,00,000) or phenylephrine less. Ester-linked LAs are rapidly hydrolyzed by
(1:20,000): plasma pseudocholinesterase and in the liver.
1. Prolongs the duration of action of LAs by Amide linked LAs are metabolized by the
slowing the rate of absorption from the site liver. They undergo extensive first pass
of administration. metabolism.
Central Nervous System 103
6. Nausea and vomiting—premedication can Sleep can be classified into two types depend-
be given to prevent this. ing on the physiological characteristics.
1. NREM (Non-rapid eye movement) sleep.
6. Epidural anesthesia: LA is injected into the
2. REM (Rapid eye movement) sleep.
spinal extradural space and it acts on the nerve
Throughout the night, NREM and REM sleep
roots. It is technically more difficult and
cycles repeat alternately for brief periods.
comparatively larger volumes of the anesthetic
Approximately one-third of our life is spent in
are needed.
sleep.
Advantages
1. Sensory blockade is 4-5 segments higher CLASSIFICATION
than motor blockade. This is useful in 1. Benzodiazepines
childbirth, as the mother has no labor pain Long-acting Diazepam,
and can still cooperate in the process of labor chlordiazepoxide,
and is conscious throughout. flurazepam, chlorazepate.
2. As there is no risk of injecting into SA space, Short-acting Temazepam, lorazepam,
there are no chances of infection. triazolam, midazolam,
nitrazepam, clonazepam,
7. Intravenous regional anesthesia: This type alprazolam
of anesthesia is useful for rapid anestheti- 2. Barbiturates Phenobarbitone,
zation of an extremity. A rubber bandage is mephobarbitone, secobarbi-
used to force the blood out of the limb (veins) tone, pentobarbitone,
and a tourniquet is applied to prevent the re- thiopentone, hexobarbitone
entry of the blood. A dilute solution of the local 3. Newer agents Zolpidem, zopiclone,
anesthetic is then injected intravenously. It eszopiclone, zaleplon
diffuses into extravascular tissues. Onset of 4. Miscellaneous Paraldehyde, chloral
anesthesia is in 2 minutes. Because of the pain hydrate, glutethimide.
produced by the tourniquet, this type of
anesthesia is used for procedures lasting less BENZODIAZEPINES (BZD)
than one hour. About 25 percent of the drug Chlordiazepoxide was the first BZD to be
enters into the systemic circulation. This type introduced into clinical medicine in 1961 and
of anesthesia is commonly used on the upper since then thousands of BZDs have been
limbs though it can also be used on the legs synthesized of which 35 are now in clinical use.
and the thighs.
Pharmacological Actions
SEDATIVE HYPNOTICS The most important actions of BZDs are on the
CNS and include—
Sedative is a drug that produces a calming or 1. Sedation and hypnosis.
quietening effect and reduces excitement. It may 2. Reduction in anxiety.
cause drowsiness. Hypnotic is a drug that induces 3. Muscle relaxation.
sleep resembling natural sleep. Both sedation and 4. Anticonvulsant effects.
hypnosis may be considered as different grades Sedation and hypnosis: BZDs hasten the onset
of CNS depression. All human beings need sleep. of sleep and increase the duration of sleep. The
Insomnia is sleeplessness. Since centuries man quality of sleep resembles natural sleep more
has sought the help of drugs and other remedies closely when compared to other hypnotics.
for insomnia. Tolerance develops to this effect gradually.
Central Nervous System 107
Anxiolytic or antianxiety effects: BZDs reduce impaired motor coordination such as driving
anxiety and aggression and thus produce a skills—therefore, while on BZDs driving should
calming effect. be avoided.
In some patients it may cause irritability and
Muscle relaxant action: BZDs reduce muscle tone
anxiety.
by a central action. Generally anxiety is associated
with an increased muscle tone and may be Tolerance and dependence: Both tolerance and risk
responsible for aches and pains in these patients. of dependence are less with BZDs as compared to
The muscle relaxation by BZDs adds to its barbiturates. Patients develop tolerance to the
beneficial effects in such patients. sedative effects. If BZDs are suddenly stopped after
Anticonvulsant effects: BZDs have anticonvulsant long-term administration, withdrawal symptoms
properties (see page 114). like anxiety, sleeplessness, irritability and
sweating can occur.
Mechanism of Action
Uses of BZDs
BZDs bind to the BZD receptors and enhance the
effect of GABA—the inhibitory neurotransmitter. 1. Insomnia: BZDs are the agents of choice in
treatment of insomina.
BZDs as hypnotics—when compared to barbiturates: 2. In anxiety states: BZDs are the most
1. BZDs induce sleep which more closely commonly used anxiolytics for the treatment
resembles natural sleep and has less of anxiety states and anxiety neuroses.
hangover. 3. As anticonvulsants: IV diazepam is the drug
2. In hypnotic doses they do not affect respiration of choice in the treatment of status
or cardiovascular functions. epilepticus. Clonazepam is used with other
3. BZDs have a higher safety margin and are antiepileptic drugs.
safer than barbiturates even in overdoses. The 4. Muscle relaxant: BZDs are centrally acting
respiratory depression in overdoses is milder. muscle relaxants used in chronic muscle
4. In case of BZD overdosage, a specific BZD spasm and spasticity.
antagonist—flumazenil can be used to reverse 5. As preaneshetic medication BZDs are useful
the symptoms. for their sedation and amnesia, anxiolytic
5. BZDs do not cause microsomal enzyme effects.
induction and therefore do not alter the blood 6. As an anesthetic intravenous diazepam or
levels of other drugs. midazolam may be used for short surgical
6. BZDs have lower abuse liability. procedures and to supplement general
Because of the above reasons, BZDs are the anesthetics.
most preferred sedative hypnotics. 7. During alcohol withdrawal: BZDs are useful
in patients during withdrawal of alcohol or
Pharmacokinetics
other sedative-hypnotics.
There are significant pharmacokinetic differences
among BZDs due to their difference in lipid Flumazenil is a BZD receptor antagonist which
solubility. competes with BZDs for the receptor and reverses
all the actions of BZDs.
Adverse Effects
Uses
BZDs are generally well tolerated. The common
side effects include drowsiness, confusion, 1. To reverse BZD sedation/anesthesia
amnesia, lethargy, ataxia, day time sedation and 2. In BZD overdosage.
108 Pharmacology for Physiotherapy
Zaleplon Uses
Zaleplon is rapidly absorbed from the gut and 1. As an anticonvulsant.
has a short t½ of about 1 hour. It is metabolized in 2. Hypnotic—rarely used.
110 Pharmacology for Physiotherapy
and coma. Formic acid has affinity for optic nerve Simple partial seizures: The symptoms depend
and causes retinal damage resulting in blindness. on the site that is affected in the cortex, e.g. if the
Death is due to respiratory failure. motor cortex representing the right thumb is
involved, there is recurrent contractions of the
Treatment right thumb. If the sensory area representing the
left palm is involved, there is numbness or
1. Correction of acidosis: As acidosis hastens
paresthesia of the left palm. This type of seizures
retinal damage, immediate correction of
last for 20-60 seconds.
acidosis with IV sodium bicarbonate
infusion helps in preventing blindness. Complex partial seizures: This is characterized
2. Patient should be kept in a dark room to by purposeless movements like lipsmaking, hand
protect the eyes. wringing or swallowing that lasts for 30 sec to 2
3. Gastric lavage should be given. minutes. Consciousness is impaired.
4. BP and ventilation should be maintained.
5. Ethyl alcohol is given as infusion. It Generalized seizures They may be:
competes with methanol for alcohol dehydro-
genase, slows the metabolism of methanol Absence seizures (petitmal): In this, there is
and thus prevents the formation of toxic sudden onset of impaired consciousness and the
metabolites. person is staring. He stops all activities and the
episode lasts for a short period usually less than
30 seconds.
ANTIEPILEPTICS
Myoclonic seizures: They involve a sudden, brief,
Epilepsy is a common neurological abnormality shock-like contraction of muscles. It may be limited
that affects about 0.5-1 percent of the population. to a part of the body or may affect the whole body.
Epilepsy is a chronic disorder characterized by
recurrent seizures often accompanied by episodes Atonic seizures (Drop attacks): They are
of unconsciousness and/or amnesia. It is a characterized by sudden loss of postural tone and
disorder of brain function. Convulsions are the head may drop for a few seconds or the person
involuntary, violent spasms series of jerking or may drop to the ground for no reason.
prolonged contractions of the skeletal muscles. Tonic-clonic seizures (Grandmal epilepsy): This
Seizure is an alteration in behavior because is characterized by sudden loss of consciousness
of abnormal firing of some brain neurons. In most followed by sustained contraction of muscles
of the cases, the cause is not known. It may be due throughout the body (known as tonic phase),
to various reasons including trauma during birth lasting for 1 minute and then, a series of jerks, i.e.
process, head injury, childhood fevers, brain periods of muscle contraction alternating with
tumors, meningitis or drug induced (e.g. periods of relaxation (clonic phase) lasting for 2-4
chlorpromazine, methylxanthines). minutes follow. CNS depression then occurs and
Seizures have been classified into partial and the person goes into sleep. Injury may occur during
generalized seizures. the convulsive episode. The episode of tonic clonic
seizures may be preceded by ‘aura’.
Partial seizures are classified as simple partial
in which there is no impairment of consciousness Status epilepticus: This is continuous or repeated
and complex partial seizures with impairment of seizures of any variety without recovery of
consciousness. consciousness between the attacks.
112 Pharmacology for Physiotherapy
Pharmacokinetics Uses
Phenytoin is poorly water-soluble—hence absorp- 1. Generalized tonic-clonic seizures and partial
tion is slow. Phenytoin is 90 percent bound to seizures (not useful in absence seizures).
plasma proteins. It is metabolized in the liver 2. Status epilepticus—phenytoin is used by
initially by first order and later by zero order slow IV injection.
Central Nervous System 113
Antiepileptic actions: Phenobarbitone has 1. Generalized tonic clonic seizures (grand mal
specific antiepileptic activity and raises the epilepsy).
seizure threshold. Primidone which is rarely used 2. Simple and complex partial seizures—
now is metabolized to phenobarbitone. especially temporal lobe epilepsy.
3. Trigeminal neuralgia and glossopharyngeal
Mechanism of action: Barbiturates enhance the neuralgia—carbamazepine is the drug of
inhibitory activity of GABA in the CNS. choice for these neuralgias and has to be
Pharmacokinetics: Oral absorption of given for several months.
phenobarbitone is slow but complete. It is a 4. Bipolar mood disorder—carbamazepine is
microsomal enzyme inducer. used as an alternative to other antidepres-
sants.
Uses: Phenobarbitone is one of the widely used
antiepileptic because of its efficacy and low cost. ETHOSUXIMIDE
It is used in:
1. Generalized tonic-clonic seizures. Ethosuximide is the primary agent for absence
2. Partial seizures. seizures. It raises the seizure threshold.
3. In neonatal jaundice (see page 14) Mechanism of action: Ethosuximide reduces the
calcium currents (T-currents) in the thalamic
CARBAMAZEPINE neurons.
Carbamazepine is closely related to imipramine.
Pharmacokinetics: Absorption is complete on
Antiseizure activity: Carbamazepine has good administration of oral dosage forms. It is
antiseizure activity. It’s mechanism of action is metabolized in the liver.
114 Pharmacology for Physiotherapy
Adverse effects: The most common adverse Valproate is also useful as a mood stabilizer
effects are nausea, vomiting, epigastric pain, in bipolar mood disorder.
gastric irritation and anorexia. These can be
avoided by starting with a low dose and gradually BENZODIAZEPINES
increasing it. CNS effects like drowsiness, fatigue,
Benzodiazepines have useful anticonvulsant
lethargy, euphoria, dizziness, headache and
properties. Diazepam is the drug of choice in
hiccough are dose-related effects. Hypersensitivity
status epilepticus. Clonazepam is a potent
reactions like rashes, urticaria, leukopenia,
antiepileptic useful in absence and myoclonic
thrombocytopenia or pancytopenia have been
seizures. But tolerance develops to its antiepileptic
reported.
effects. Clobazam causes less sedation and is
Uses: Ethosuximide is the drug of choice for effective in most types of epilepsies.
absence seizures.
NEWER ANTIEPILEPTICS
VALPROIC ACID Gabapentin is a highly lipid soluble analog of
Valproic acid (salt→sodium valproate) is a very GABA which was designed to cross the BBB. It is
effective antiepileptic drug useful in many types effective in tonic clonic seizures. Its exact
of epilepsies including absence seizures, partial mechanism of action is not known, but it does not
and generalized tonic-clonic seizures. act directly on GABA receptors. It is well tolerated
and does not influence the plasma concentrations
Mechanism of action: Valproic acid acts by of other antiepileptics.
multiple mechanisms. Adverse effects include ataxia, fatigue,
1. It enhances the level of GABA by: drowsiness and dizziness. Tolerance develops to
i. Increasing the synthesis of GABA—by these effects in 1-2 weeks. Gabapentin is used in
increased activity of GABA synthetase combination with other antiepileptic drugs, as an
enzyme. add on drug in partial seizures. It is also used in
ii. Decreasing the metabolism of GABA—by migraine, neuropathic pain and in bipolar mood
inhibiting GABA transaminase enzyme. disorder.
2. Like phenytoin, it blocks the sodium channels.
Pregabalin is a prodrug, which is more potent
3. Like ethosuximide, it suppresses the calcium
than gabapentin.
‘T’ currents in the hypothalamus.
Lamotrigine has a broad spectrum of
Adverse effects: Gastrointestinal symptoms like antiepileptic activity. It inhibits the sodium
nausea, vomiting, epigastric distress occur channels and also inhibits the release of the
initially. Tremors, sedation, ataxia, rashes and excitatory amino acids like glutamate. It is
alopecia are rare. Valproic acid can cause completely absorbed from the gut. Lamotrigine
fulminant hepatitis—though rare can be fatal. may cause skin rashes, nausea, ataxia and
Hence careful monitoring of liver functions is dizziness. It is used either alone or with other
mandatory. Valproic acid is teratogenic, it can drugs in partial and generalized seizures.
cause neural tube defects.
Vigabatrin is a GABA analog which acts by
Uses: Useful in partial and generalized seizures. irreversibly inhibiting the enzyme GABA
Valproic acid is particularly useful in absence transaminase thereby raising brain GABA levels.
seizures. In patients with both absence seizures It can cause depression in some patients.
and generalized tonic-clonic attacks, valproate is Vigabatrin is useful in patients not responding to
the drug of choice. other antiepileptics.
Central Nervous System 115
Levetiracetam a pyrrolidine, is effective against Lacosamide has been recently introduced for the
partial and secondarily generalized seizures. Its treatment of partial seizures. It acts on the sodium
mechanism of action is not known. It is not an channels, is completely absorbed when given
enzyme inducer - no related drug interactions. orally and can cause headache, nausea, dizziness
Levetiracetam can be used as an add-on drug in and blurred vision. It can be used as add-on drug
refractory partial seizures. in partial seizures in patients above 16 years of
age.
Tiagabine
• Newer antiepileptics include gabapentin,
Tiagabine a GABA analog, inhibits the reuptake pregabalin, lamotrigine, vigabatrin,
of GABA into neurons and thereby enhances levetiracetam, tiagabine, topiramate,
extracellular GABA levels. It may cause felbamate, zonisamde and locosamide.
drowsiness and dizziness. Tiagabine can be used • Gabapentin, vigabatrin and lamotrigine act
as add-on drug for refractory partial seizures. by influencing GABA.
• Lamotrigine, topiramate and zonisamide act
Topiramate a monosaccharide, acts by multiple on sodium channels.
mechanisms. It blocks the sodium channels, • The newer antiepileptics are indicated as add
enhances GABA receptor currents, blocks AMPA on drugs in refractory epilepsies.
receptors (glutamate receptor). It is effective in
partial and generalized seizures. Topiramate can
be used as add-on therapy in refractory epilepsy. Treatment of Epilepsies (Table 6.3)
Felbamate an analogue of meprobamate is found Most patients with epilepsy require prolonged
to have good antiepileptic action. It blocks the treatment, side effects from antiepileptics are
NMDA receptors in addition to weak sodium respected because of the long duration of treatment
channel blocking effect. But felbamate can needed.
sometimes cause serious adverse effects like
Febrile convulsions: Two to four percent of
aplastic anemia and hepatitis because of which it
children experience convulsions during fever; of
is employed only in refractory epilepsy.
them 2-3 percent become epileptics. Treatment is
Zonisamide a sulfonamide derivative acts by controversial. Children < 18 months developing
inhibiting the T type Ca++ currents and also by febrile convulsions, those with neurological
blocking Na+ channels. It is well tolerated and is abnormalities and those with seizures lasting for
indicated in refractory partial seizures. > 15 minutes, complex seizures—all these have
Adverse reactions: As large amounts (95%) of Amantadine is an antiviral drug. It enhances the
levodopa is converted to dopamine in the release of DA in the brain and diminishes the re-
periphery, several adverse effects are expected. uptake of DA. The response starts early and its
Nausea, vomiting, postural hypotension, adverse effects are minor. Large doses produce
tachycardia and occasionally arrhythmias can insomnia, dizziness, vomiting, postural hypo-
occur. Tolerance develops to these effects after tension, hallucinations, ankle edema and livido
sometime. Behavioral effects like anxiety, reticularis.
depression, hallucinations and sometimes Amantadine is used in mild cases of
psychosis can occur. parkinsonism. It can also be used along with
Abnormal involuntary movements like facial tics, levodopa.
grimacing, choreoathetoid movements of the limbs Dopamine receptor agonists: Bromocriptine and
may develop after a few months of use and require pergolide are ergot derivatives having dopamine
reduction in the dose of levodopa. agonistic activity. The newer agents ropinirole
Fluctuation in response to levodopa can occur and pramipexole are selective D2 agonists, are
after 2-5 years of use—known as ‘on-off’ better tolerated, quickly attain therapeutic levels
phenomenon—where the patient has alternately and adverse effects are milder except that they
good response and severe disease. may cause some sleep disorders.
Dopamine agonists are all longer acting
Uses: Levodopa is the most effective drug in because of which they are useful in the treatment
idiopathic parkinsonism but is not useful in drug of ‘on-off’ phenomenon.
induced parkinsonism. Adverse effects include nausea, vomiting,
Drug interactions hallucinations and skin eruptions. Ergot
1. Pyridoxine enhances the peripheral derivatives can cause postural hypotension and
decarboxylation of levodopa and thus ‘first dose phenomenon’—that is sudden
reduces its availability to the CNS. cardiovascular collapse.
2. Phenothiazines, metoclopramide and DA agonists are used:
reserpine are DA antagonists. They reverse 1. In the treatment of ‘on-off’ phenomenon.
the effects of levodopa. 2. As alternatives in the initial treatment of
Carbidopa and benserazide are peripheral dopa parkinsonism.
decarboxylase inhibitors. When carbidopa or
Lisuride and pergolide are similar to bromocriptine.
benserazide are given with levodopa, they prevent
the formation of dopamine in the periphery. They
Drugs that Inhibit DA Metabolism
do not cross the BBB and hence allow levodopa to
reach the CNS. The combination is synergistic and Selegiline (Deprenyl) is a selective MAO-B
therefore levodopa is always given with inhibitor. MAO-B is present in DA containing
carbidopa/benserazide. regions of the CNS. Selegiline prolongs the action
of levodopa by preventing its destruction.
Advantages of combining carbidopa/benserazide—
Selegiline may delay the progression of
with levodopa.
parkinsonism.
1. Dose of L-dopa can be reduced by 75 percent.
Adverse effects include nausea, postural
2. Response to L-dopa appears earlier.
hypotension, confusion and hallucinations.
3. Side effects like vomiting and tachycardia are
largely reduced. Uses: Mild cases of parkinsonism are started on
4. Pyridoxine does not interfere with treatment. selegiline. It is also used along with levodopa.
118 Pharmacology for Physiotherapy
use. But because they were equally abused, efforts receptors are abundant in the CNS and other
were made to isolate the analgesic property, i.e. to tissues. The opioid receptors are mu (μ) kappa (κ)
obtain an opioid that is only analgesic and has and delta (δ). It is found that there are 3 families of
no euphoric effects. In the process, various endogenous opioid peptides released in the body
agonists, antagonists and partial agonists were viz enkephalins, endorphins and dynorphins. This
synthesized. ’Opioid’ is the term used for drugs indicates that we have a natural system in the
with morphine-like actions. They were earlier body that releases various opioid peptides in
called narcotic analgesics. response to pain.
Most pharmacological effects of opioids
CLASSIFICATION including analgesia, sedation, euphoria, respi-
ratory depression, miosis and constipation are all
1. Agonists: Natural opium alkaloids, e.g.
due to stimulation of µ (mu) opioid receptors.
Morphine, codeine, synthetic opioids, e.g.
Pethidine, methadone.
Pharmacological Actions
2. Antagonists: Naloxone, naltrexone, nalmefene.
3. Mixed agonist-antagonists: Pentazocine, Central nervous system
nalbuphine, butorphanol, buprenorphine, 1. Analgesia: Morphine is a potent analgesic
nalorpine. and relieves pain without loss of conscious-
ness. Dull aching visceral pain is relieved better
Chemically the opium alkaloids
than sharp pricking pain. In higher doses it
can be grouped into
relieves even the severe pain as that of biliary
1. The phenanthrene group: Morphine, codeine, colic. Morphine alters both the perception and
thebaine. reaction to pain. It raises the pain threshold
2. The benzylisoquinoline group: Papaverine, and thus increases the capacity to tolerate
noscapine, narcine. pain. Further it alters the emotional reaction
Opioids can also be classified to pain.
depending on their source as Euphoria and sedation contribute to its
analgesic effects.
1. Natural opium alkaloids: Morphine, codeine,
2. Euphoria, sedation and hypnosis: Morphine
noscapine.
produces a feeling of well-being termed
2. Semisynthetic derivatives: Heroin, oxymor-
euphoria. It is this effect which makes it an
phone, pholcodeine.
important drug of abuse. Rapid intravenous
3. Synthetic opioids: Pethidine, fentanyl,
injection of morphine produces a warm
diphenoxylate, loperamide, methadone,
flushing of the skin and an immensely
dextropropoxyphene and tramadol.
pleasurable sensation in the lower abdomen
Morphine is the most important alkaloid of
lasting for about 45 seconds and is known as
opium. Many new opioids with actions similar to
‘high’, ‘rush’ or ‘kick’. The person loses
morphine have been synthesized. But none of
rational thinking and is lost in colorful day
them are superior to morphine as an analgesic.
dreams. It also produces drowsiness, a calming
Morphine is discussed as the prototype of the
effect, inability to concentrate, feeling of
group.
detachment and indifference to surroundings.
But the effects of morphine may not be
Mechanism of Action pleasurable in all. A person has to learn to
Morphine and other opioids produce their effects experience its pleasurable effects. It may
by acting on specific opioid receptors. These produce dysphoria in some.
120 Pharmacology for Physiotherapy
3. Respiration: Morphine produces significant spasms of the intestine. The tone of the sphincters
respiratory depression. It directly depresses is increased leading to spasm. The intestinal
the respiratory center in the brainstem. This motility is markedly diminished. Thus, reduced
action is dose dependent. Death from secretions and motility result in marked
morphine poisoning is almost always due to constipation.
respiratory arrest.
Sedation and indifference to surroundings Other Smooth Muscles
add to the respiratory depression.
Biliary tract: Morphine causes spasm of the
4. Cough center: It directly depresses the cough
sphincter of Oddi and may cause biliary colic.
center and thereby suppresses cough.
5. Nausea and emesis: Morphine directly Urinary bladder and ureter: Tone and contractions
stimulates the chemoreceptor trigger zone of the ureter is increased; tone of external sphincter
(CTZ) in the medulla causing nausea and and volume of the bladder are increased. Opioids
vomiting. In higher doses it depresses the inhibit urinary voiding reflex. All these result in
vomiting center and hence there is no vomiting urinary retention especially in elderly male with
in poisoning. Therefore, emetics should not be prostatic hypertrophy.
tried in poisoning.
Bronchi: Morphine causes release of histamine
6. Pupils: Morphine produces constriction of
from the mast cells leading to bronchoconstriction.
pupil. In higher doses a characteristic pinpoint
This can be dangerous in asthmatics.
pupil is seen by a central effect.
7. Vagus: Morphine stimulates vagal center
Neuroendocrine Effects
causing bradycardia.
8. Heat regulation: Opioids act on heat-regulat- Morphine inhibits the release of gonadotrophin-
ing center and body temperature falls slightly. releasing hormone and CRF.
9. Excitatory effect: In high doses opioids
produce convulsions. They may increase the Pharmacokinetics
excitability of the spinal cord.
Given orally, absorption of morphine is slow and
Cardiovascular system: In therapeutic doses, incomplete and undergoes extensive first pass
morphine produces hypotension by direct metabolism. Bioavailability is 20 to 40 percent.
peripheral vasodilatation. Given subcutaneously, onset of action is within
In higher doses it causes depression of the 15-20 min, duration of action is 3-5 hr. Morphine
vasomotor center and also brings about histamine is metabolized in the liver by glucuronide
release, both causing a fall in BP. Postural conjugation.
hypotension and fainting may occur.
Adverse Effects
GIT: Opioids decrease the motility of the gut.
Morphine can produce a wide range of adverse
Stomach: Gastric motility is decreased and gastric
effects like-nausea, vomiting, dizziness, mental
acid secretion is reduced. Opioids increase the
clouding, respiratory depression, constipation,
tone of the antrum and first part of the duodenum
dysphoria, urinary retention and hypotension.
which also result in delayed emptying by as much
Allergic reactions including skin rashes,
as 12 hours.
pruritus and wheal at the site of injection and
Intestines: Morphine reduces all intestinal rarely anaphylaxis may be seen. This is because
secretions, delays digestion of food in the small morphine liberates histamine. It is a drug of
intestine; resting tone is increased. There can be dependence.
Central Nervous System 121
Tolerance and dependence: Repeated vomiting and fever. Tincture of opium is started
administration of morphine results in the and gradually withdrawn.
development of tolerance to some of its effects
including respiratory depression, analgesia, Management of Addiction
sedation and euphoriant effects and other CNS Morphine is slowly withdrawn over several days
depressant effects. Constipation and miosis show and oral methadone is given.
no tolerance. Though lethal dose of morphine is Advantages of methadone administration are:
about 250 mg, addicts can tolerate morphine in 1. Methadone is effective orally and by this route
grams. An addict needs progressively higher no ‘kick’ is experienced.
doses to get his ‘kick’ or ‘rush’. Patients in pain 2. It is more potent, long-acting and prevents
can also tolerate a higher dose of morphine. Cross- withdrawal symptoms.
tolerance is seen among different opioids. The dose is adjusted based on the degree of
Opium has been a drug of addiction for many dependence. Methadone is then slowly with-
centuries. Its ability to produce euphoria makes it drawn.
a drug of addiction. Opioids produce both Most addicts can be completely withdrawn
psychological and physical dependence. Sudden from opioids in about 10 days though mild
withdrawal of opioids or administration of opioid withdrawal symptoms still remain. Symptoms like
antagonists produce significant withdrawal insomnia, malaise, restlessness, irritability,
symptoms in such dependent individuals. fatigue and GI hyperactivity may last up to several
Manifestations are lacrimation, sweating, months.
yawning, anxiety, apprehension, restlessness, Clonidine a central α2 agonist can suppress
running nose and tremors—seen 8-12 hr after the some of the autonomic withdrawal symptoms like
last dose. The person craves for the drug. As the anxiety, nausea, vomiting and diarrhea. It is given
syndrome progresses, fever, insomnia, abdominal for 7-10 days and withdrawn over 3-4 days. Night
colic, severe sneezing, violent yawning, diarrhea, time sedation with a hypnotic is helpful.
blurring of vision due to mydriasis, hypertension,
Uses of Morphine
severe dehydration, gooseflesh, palpitation and
cardiovascular collapse can occur. There is severe Dose: Morphine 10 to 20 mg IM/SC; 20 mg tab
weakness, depression and irritability. Goose flesh (ethyl morphine) is now available for oral use.
is due to pilomotor activity; skin resembles that of 1. Analgesic: Morphine is one of the most potent
a plucked turkey. Hence the word ‘cold turkey’ is analgesics available. It provides symptomatic
used for sudden withdrawal. Abdominal cramps, relief of pain without affecting the underlying
pain in the bones and muscles of the back and disease. It is an excellent analgesic for severely
limbs are also characteristic. painful conditions such as acute myocardial
Withdrawal symptoms are generally not fatal. infarction, fractures, burns, pulmonary
Administration of a suitable opioid, dramatically embolism, terminal stages of cancer, acute
and completely reverses the symptoms of pericarditis, spontaneous pneumothorax and
withdrawal. Without treatment, symptoms postoperative pain. In excruciating pain,
disappear in 7-10 days. morphine can be given IV.
In myocardial infarction, morphine
Withdrawal in the newborn: Babies born to mothers relieves pain and thereby anxiety. As a result
who were addicts prior to delivery—will also be reflex sympathetic stimulation is reduced.
dependent. Withdrawal symptoms seen are • Morphine is given with atropine to relieve
irritability, excessive crying, tremors, frantic renal and biliary colic. Atropine relieves
suckling of fists, diarrhea, sneezing, yawning, spasm.
122 Pharmacology for Physiotherapy
• CNS effects of pentazocine are similar to Dose: 0.3-0.6 mg SC, IM or sublingual (oral not
morphine. Euphoria is seen only in low doses. available).
With higher doses—dysphoria can occur due
Uses: Chronic pain like terminal cancer.
to κ receptor stimulation.
• Sedation and respiratory depression are less. Butorphanol is similar to pentazocine.
• It has weak antagonistic properties at μ
Nalorphine is also an agonist-antagonist. At low
receptors.
doses, it is a good analgesic. But it causes
• Tolerance and dependance develop on
dysphoria (κ agonist) and respiratory depression
repeated use.
even in low doses. Hence it cannot be used as an
• CVS—in contrast to morphine, pentazocine
analgesic. At high doses it acts as an antagonist
causes ↑BP and ↑heart rate and thereby
and counters all the actions of opioids.
increases cardiac work. It is therefore not
suitable in MI. Uses: Nalorphine may be used in acute opioid
• Biliary spasm and constipation are less severe. poisoning. It can also be used for the diagnosis of
• Pentazocine can be given both orally and opioid addiction.
parenterally. It undergoes first pass
metabolism. OPIOID ANTAGONISTS
• Dose 50-100 mg oral; 30-60 mg IM (FORTWIN).
Naloxone is a pure antagonist—acts as a
Adverse effects: Sedation, sweating, dizziness, competitive antagonist to all types of opioid
nausea, dysphoria with anxiety, nightmares and receptors. In normal individuals, it does not
hallucinations, which are unpleasant are seen produce any significant actions. But in opium
above 60 mg. As it is an irritant, IM injection can addicts, given IV, it promptly antagonizes all the
be painful and cause sterile abscesses. actions of morphine including respiratory
depression and sedation and precipitates
Uses: Pentazocine is a commonly used opioid withdrawal syndrome. It also blocks the action of
analgesic especially in postoperative and chronic endogenous opioid peptides—endorphins,
pain—abuse liability is less than morphine. enkephalins and dynorphins. It blocks the
Nalbuphine is an agonist-antagonist—like penta- analgesia produced by placebo and acupuncture.
zocine. It is a good analgesic. Though it produces This suggests that endogenous opioid peptides
respiratory depression like morphine, it has a are responsible for analgesia by these methods.
ceiling effect at 30 mg, i.e. an increase in dose Given orally it undergoes first pass metabolism
beyond 30 mg does not increase respiratory and is metabolized by the liver. Duration of action
depression further. Higher doses produce is 3-4 hours.
dysphoria.
Uses
Uses: As analgesic—10-20 mg IM.
1. Naloxone is the drug of choice for morphine
Buprenorphine is a highly lipid soluble synthetic overdosage.
opioid. It is a partial μ agonist, 25 times as potent 2. It is also used to reverse neonatal asphyxia
as morphine. Though onset of action is slow, due to opioids used in the mother during labor.
duration of analgesia is long. Other CNS effects 3. Naloxone can also be used for the diagnosis
are similar to morphine while respiratory depres- of opioid dependence—it precipitates
sion is less. Patients exhibit lower degree of withdrawal in addicts.
tolerance and dependence liability. Withdrawal 4. Hypotension seen during shock could be due
syndrome appears late and is mild. to endogenous opioids released during such
126 Pharmacology for Physiotherapy
in vague visceral pain, aspirin is relatively respiratory center. Salicylates also directly
ineffective. stimulate the medullary respiratory center.
The pain is relieved without euphoria and Both these actions increase the rate and depth
hypnosis. Hence there is no development of of respiration. These effects are dose depen-
tolerance and dependance. But aspirin is a dent.
weak analgesic when compared to morphine. As a result of this stimulation of respiration,
plasma CO2 is washed out leading to respi-
2. Antipyretic action: In fever, salicylates bring
ratory alkalosis. With toxic doses, the
down the temperature to normal level. But, in
respiratory center is depressed leading to
normal individuals, there is no change in
respiratory failure.
temperature.
In fever, pyrogen—a protein, circulates in 5. Acid-base and electrolyte balance: In anti-
the body and this increases the synthesis of inflammatory doses, salicylates produce
PGs in the hypothalamus, thereby raising its significant respiratory stimulation so that CO2
temperature set point. The thermostatic is washed out resulting in respiratory
mechanism in the hypothalamus is thus alkalosis; pH becomes alkaline. This is
disturbed. Aspirin inhibits PG synthesis in the compensated by increased excretion of HCO3–
hypothalamus and resets the thermostat at the in urine.
normal level bringing down the temperature. With toxic doses, salicylates depress the
Enhanced sweating and cutaneous respiratory center directly. As a result, CO2
vasodilatation promote heat loss and assist in accumulates, plasma CO2 level rises and pH
the antipyretic action. decreases, i.e. there is acidosis.
Toxic doses also depress vasomotor
3. Anti-inflammatory action: At higher doses of center. This vasomotor depression impairs
4-6 gm/day, aspirin acts as an anti-inflam- renal function resulting in accumulation of
matory agent. Signs of inflammation like strong acids of metabolic origin like lactic,
tenderness, swelling, erythema and pain are pyruvic and acetoacetic acids.
all reduced or suppressed. But, the progression The above effects are accompanied by
of the disease in rheumatoid arthritis, rheu- dehydration due to:
matic fever or osteoarthritis is not affected. • Water lost in urine with HCO3–, Na+ and K+
Once again the mechanism of action is PG • Increased sweating
synthesis inhibition—PGs present in inflam- • Water lost during hyperventilation.
matory tissue are responsible for edema, Thus high doses cause severe dehydration
erythema and pain. In addition, aspirin also with acidosis.
interferes with the formation of chemical medi-
6. Metabolic effects: Salicylates enhance the
ators of the kallikrein system. As a result, it
cellular metabolism. More of O2 is used and
decreases the adherence of granulocytes to the
more CO2 is produced, especially in skeletal
damaged vasculature, stabilizes lysomes and
muscles—leading to increased heat produc-
decreases the migration of the polymorpho-
tion. Glucose utilization is increased leading
nuclear leukocytes and macrophages into the
to mild hypoglycemia.
site of inflammation.
In toxic doses, hyperpyrexia, increased
4. Respiration: In therapeutic doses of 4-6 g/ protein catabolism, negative nitrogen balance
day—salicylates increase consumption of and hyperglycemia (due to central sympathetic
oxygen by skeletal muscles. As a result there stimulation which increases adrenaline levels)
is ↑CO2 production. The ↑CO2 stimulates can occur.
128 Pharmacology for Physiotherapy
7. Pregnancy and infancy: Aspirin when taken in frusemide is given along with IV fluids.
full term pregnancy delays the onset of labor Sodium bicarbonate make salicylates water
due to inhibition of PG synthesis (PGs play an soluble and increases their excretion through
important role in the initiation of labor). kidneys.
Premature closure of ductus arteriosus may
occur in the fetus resulting in portal hyper- Precautions and Contraindications
tension. It can also increase postpartum
bleeding due to inhibition of platelet aggre- Peptic ulcer, liver diseases, bleeding tendencies,
gation. children suffering from viral fever and pregnancy
8. Salicylism: Prolonged administration of are contraindications for the use of salicylates.
salicylates as in the treatment of rheumatoid Treatment with NSAIDs should be stopped one
arthritis may lead to chronic salicylate week before any surgery.
intoxication termed ‘Salicylism’. The syn-
drome is characterized by headache, vertigo, Preparations
dizziness, tinnitus, vomiting, mental con- Preparations and dosage of salicylates (Table 6.4).
fusion, diarrhea, sweating, difficulty in
hearing, thirst and dehydration. These USES
symptoms are reversible on withdrawal of
1. As analgesic for headache, backache,
salicylates.
myalgias, arthralgias, neuralgias, toothache
Acute salicylate intoxication: Poisoning may be and dysmenorrhea. The NSAIDs are beneficial
accidental or suicidal. It is more common in in a variety of painful conditions of integu-
children, 15-30 g is the fatal dose of aspirin. mental origin.
2. Fever: NSAIDs are useful for the symptomatic
Symptoms and signs: Dehydration, hyperpyrexia, relief of fever.
GI irritation, vomiting, sometimes hematemesis, 3. For inflammatory conditions: Aspirin is effective
acid-base imbalance, restlessness, delirium, in a number of inflammatory conditions such
hallucinations, metabolic acidosis, tremors, as arthritis and fibromyositis.
convulsions, coma and death due to respiratory
4. Acute rheumatic fever: In a dose of 4-6 g/day,
failure and cardiovascular collapse.
aspirin brings about a dramatic relief of signs
Treatment is symptomatic and includes:
and symptoms in 24 to 48 hr. The dose is
1. Stomach wash lavage to eliminate unabsorbed
reduced after 4-7 days and maintenance doses
drugs.
of 2-3 g/day are given for 2-3 weeks.
2. IV fluids to correct acid-base imbalance and
5. Rheumatoid arthritis: Aspirin relieves pain,
dehydration.
reduces swelling and redness of joints in
3. Temperature is brought down by external
rheumatoid arthritis. Joint mobility improves,
cooling with alcohol or cold water sponges.
fever subsides, and there is a reduction in
4. If there is bleeding, blood transfusion and
morning stiffness. But NSAIDs do not alter the
vitamin K are needed.
progress of the disease. The relief is only
5. The IV fluids should contain Na+, K+, HCO3–
symptomatic.
and glucose (to treat hypokalemia and
acidosis). Dose: 4-6 g/day in 4-6 divided doses.
6. In severe cases, forced alkaline diuresis with 6. Osteoarthritis: It provides symptomatic relief
sodium bicarbonate and a diuretic like in osteoarthritis.
130 Pharmacology for Physiotherapy
Adverse effects: Treatment with gold is aplastic anemia, a variety of autoimmune diseases
associated with several adverse effects and only including lupus erythematosus, thyroiditis and
60 percent of patients remain on treatment at the hemolytic anemia. Anorexia, nausea, vomiting,
end of 2 years. loss of taste perception and alopecia may also be
seen.
Adverse effects include:
1. On skin and mucous membrane: Dermatitis, Chloroquine and hydroxychloroquine: These
pruritus, stomatitis, pharyngitis, glossitis, antimalarial drugs are found to be useful in mild
gastritis, colitis and vaginitis. A grey blue non-erosive rheumatoid arthritis. They induce
pigmentation on exposed parts of the skin may remission in 50 percent of patients. They are less
be seen. effective but are better tolerated than gold.
2. Renal toxicity: Hematuria, glomerulonephritis. Mechanism of action is not exactly understood
3. Nervous system: Encephalitis, peripheral but they are known to depress cell-mediated
neuritis. immunity.
4. Liver: Hepatitis, cholestatic jaundice.
Toxicity: Chloroquine and hydroxychloroquine
5. Blood: Thrombocytopenia, leukopenia,
accumulate in tissues leading to toxicity. The most
agranulocytosis, aplastic anemia.
significant side effect is the retinal damage on
6. CVS: Postural hypotension.
long-term use. This toxicity is less common and
7. Lungs: Pulmonary fibrosis.
reversible with hydroxychloroquine which is
Contraindications: Kidney, liver and skin diseases; therefore preferred over chloroquine in
pregnancy and blood dyscrasias. rheumatoid arthritis. Every 3 months eyes should
be tested. Other adverse effects include myopathy,
Uses neuropathy and irritable bowel syndrome.
1. Rheumatoid arthritis—gold is used in active Dose: Hydroxychloroquine 400 mg/day for 4-6
arthritis that progresses even after treatment weeks; maintenance dose is 200 mg/day.
with an adequate course of NSAIDs, rest and
physiotherapy. In most patients gold salts Sulphasalazine is a compound of sulphapyridine
arrest the progression of the disease, improve and 5-amino salicylic acid. In the colon,
grip strength, reduce morning stiffness and sulphasalazine is split by the bacterial action and
prevent involvement of unaffected joints. sulphapyridine gets absorbed. This has anti-
Gold is also beneficial in: inflammatory actions though the mechanism is
2. Juvenile rheumatoid arthritis. not known. Adverse effects include gastrointestinal
3. Psoriatic arthritis. upset and skin rashes.
4. Pemphigus. Abatacept inhibits T cell activation and can be
5. Lupus erythematosus. used alone or with other drugs as an I.V. infusion.
d-penicillamine is an analog of the amino acid There is a clinical improvement but can increase
cysteine and a metabolite of penicillin. It is a the risk of infection particularly upper respiratory
chelating agent that chelates copper. Its actions infection.
and toxicities are similar to gold but is less
TNF blocking agents: Cytokines, particularly
effective than gold. Hence it is not preferred. It is
tumor necrosis factor (TNF) plays an important
used as an alternative to gold in early, mild and
role in the process of inflammation. TNF produced
non-erosive disease.
by macrophages and activated T cells, acts through
Adverse effects include drug fever, skin rashes, TNF receptors to stimulate the release of other
proteinuria, leukopenia, thrombocytopenia, cytokines. TNF blocking drugs are found to be
Central Nervous System 137
metabolism. As uric acid is poorly water soluble, Adverse effects are dose related. Nausea,
it gets precipitated—especially at low pH and vomiting, diarrhea and abdominal pain are the
deposited in the cartilages of joints and ears, earliest side effects and may be avoided by giving
subcutaneous tissues, bursae and sometimes in colchicine intravenously. Anemia, leukopenia and
kidneys. An acute attack of gout occurs as an alopecia may be seen. In high doses hemorrhagic
inflammatory reaction to crystals of sodium urate gastroenteritis, nephrotoxicity, CNS depression,
deposited in the joint tissue. There is infiltration muscular paralysis and respiratory failure can
of granulocytes which phagocytize the urate occur.
crystals and release a glycoprotein that causes
joint destruction. The joint becomes red, swollen, Uses
tender and extremely painful.
1. Acute gout—colchicine 1 mg orally initially
Secondary hyperuricemia may be drug
followed by 0.5 mg every 2-3 hours relieves
induced or may occur in lymphomas and
pain and swelling within 12 hours. But
leukemias. Gout may also be due to decreased
diarrhea limits its use.
excretion of uric acid.
2. Prophylaxis—Colchicine may also be used for
Strategies in the treatment of gout is either to
the prophylaxis of recurrent episodes of gouty
decrease the biosynthesis of uric acid or enhance
arthritis.
the excretion of uric acid.
NSAIDs afford symptomatic relief in the treatment
Drugs Used in Gout of gout. Indomethacin is the most commonly used
agent in acute gout. Piroxicam, naproxen and other
In acute gout: Colchicine,
newer NSAIDs are also used. They relieve an
NSAIDs.
acute attack in 12-24 hours and are better tolerated
In chronic gout: Uric acid synthesis Allopurinol
than colchicine. But NSAIDs are not recom-
inhibitor
mended for long-term use due to their toxicity.
Uricosuric drugs Probenecid,
Sulphin- Allopurinol is an analog of hypoxanthine and
pyrazone. inhibits the biosynthesis of uric acid.
Colchicine is an alkaloid of Colchicum autumnale. Mechanism of action: Purine nucleotides are
It is a unique anti-inflammatory agent effective degraded to hypoxanthine. Uric acid is produced
only against gouty arthritis. It is not an analgesic. as shown in Figure 6.1. Allopurinol and its
metabolite alloxanthine both inhibit the enzyme
Actions: In gout, colchicine is highly effective in
xanthine oxidase and thereby prevent the
acute attacks and it dramatically relieves pain
synthesis of uric acid. The plasma concentration
within a few hours.
of uric acid is reduced.
Mechanism of action: Colchicine inhibits the
migration of granulocytes into the inflamed area
and the release of glycoprotein by them.
Other actions: Colchicine binds to microtubules
and arrests cell division in metaphase. It increases
gut motility by neurogenic stimulation.
Pharmacokinetics: Colchicine is rapidly absorbed
orally, metabolized in the liver and undergoes
enterohepatic circulation. Fig. 6.1: Biosynthesis of uric acid
Central Nervous System 139
Local anesthetic: CPZ has local anesthetic intramuscularly and the response is seen in 24
properties—but is not used for the purpose since hours. In chronic psychosis it takes 2-3 weeks of
it is an irritant. treatment to obtain the response.
1. Psychiatric conditions: Psychoses including
Kidney: CPZ depresses ADH secretion and has
schizophrenia and organic brain syndromes
weak diuretic effects.
like delirium and dementia all respond to
Tolerance develops to the sedative and
antipsychotics.
hypotensive actions while no tolerance is seen to
2. Nausea, vomiting: CPZ is a good antiemetic and
the antipsychotic actions.
is used in vomiting due to radiation sickness
Pharmacokinetics: CPZ is incompletely and drug induced vomiting.
absorbed following oral administration and also 3. Hiccough: CPZ can control intractable
undergoes significant first pass metabolism hiccough though the mechanism of action is
(bioavailability is 30%). It is highly protein bound; not known.
has a t½ of 20 to 24 hr and is therefore given once 4. Other neuropsychiatric syndromes: Neuroleptics
a day. are useful in the treatment of several syndromes
with psychiatric features like psychoses
Adverse reactions: Antipsychotics have a high associated with chronic alcoholism, mania,
therapeutic index and are fairly safe drugs. bipolar mood disorders and Huntington’s
1. Cardiovascular and autonomic effects— disease.
postural hypotension, palpitation, blurred
vision, dry mouth, constipation, nasal
Atypical Antipsychotics
stuffiness and urinary retention.
2. CNS effects—drowsiness and mental con- Atypical antipsychotics have the following
fusion, a variety of neurological syndromes advantages over conventional antipsychotics:
involving the extrapyramidal system includ- 1. Very low incidence of extrapyramidal side
ing parkinsonism, dyskinesias, dystonias, effects.
akathesia, perioral tremors and malignant 2. Sedation is low.
neuroleptic syndrome are troublesome side 3. No endocrine side effects, i.e. no galactorrhea
effects. and gynecomastia.
3. Endocrine disturbances—gynecomastia, 4. They are effective in patients not responding
amenorrhea and galactorrhea. to conventional antipsychotics.
4. Hypersensitivity reactions—jaundice,
agranulocytosis and skin rashes. Clozapine: In addition to blocking DA receptors,
clozapine also blocks 5-HT2, α adrenergic and
Drug interactions: Neuroleptics enhance the muscarinic receptors. Clozapine is an effective
sedative effects of CNS depressants, and the effects antipsychotic.
of anticholinergic drugs and alpha blockers. When
combined with these groups of drugs, the effects Disadvantage: May cause agranulocytosis in some
may be additive. patients which can be fatal. Hence use should be
Neuroleptics inhibit the actions of dopamine restricted to patients who are not responding to
agonists and L-dopa. other drugs. Clozapine can also cause sedation,
weight gain and hypotension.
Uses Olanzepine: It has the advantage that it causes
Neuroleptics are given orally (chlorpromazine no EPS dysfunction and no agranulocytosis has
100-800 mg). In acute psychosis they may be given been reported.
142 Pharmacology for Physiotherapy
Risperidone: It blocks serotonin and dopamine after 2-3 weeks of treatment, elevation of mood
receptors and is a commonly used antipsychotic. occurs; the patient shows more interest in the
surroundings and the sleep pattern becomes
Advantages
normal.
1. At low doses no EPS dysfunction.
Mechanism of action: TCAs block the reuptake
2. Low sedation.
of amines (noradrenaline or 5-HT) into the
presynaptic terminal, and thereby prolong
ANTIDEPRESSANTS their action on the receptors. Thus they
potentiate amine neurotransmission in the
Affective disorders are a group of psychoses
CNS.
associated with changes of mood, i.e. depression
and mania. 2. CVS : Postural hypotension and tachycardia
(due to blockade of α 1 adrenergic and
Depression is a common psychiatric disorder and muscarinic receptors) can be severe in
could be: overdosage.
1. Reactive: Due to distressing circumstances in
3. ANS: TCAs have anticholinergic properties
life.
and cause dry mouth, blurred vision, consti-
2. Endogenous: Major depression due to a
pation and urinary retention.
biochemical abnormality in the brain.
3. Bipolar mood disorder: Mania and depres-
Pharmacokinetics
sion occur alternately causing cyclic mood
swings. TCAs are rapidly absorbed, highly protein bound
Endogenous depression is thought to be due and metabolized in the liver. They have a long t½
to deficiency of monoamine activity (NA, 5-HT) and can be given once daily.
in the CNS.
Adverse Effects
Drugs Used in Affective Disorders
Sedation, postural hypotension, tachycardia,
Classification sweating and anticholinergic side effects like dry
mouth, constipation, blurred vision and urinary
1. Tricyclic antidepressants (TCA)—Imipramine,
retention are relatively common. TCA may
desipramine, amitriptyline, nortriptyline
precipitate convulsions in epileptics; may cause
doxepin.
hallucinations and mania in some patients. Many
2. Selective serotonin (5-HT) reuptake inhibitors
TCAs may also cause weight gain due to increased
(SSRI)—Fluoxetine, fluoxamine, paroxetine,
appetite.
citalopram, sertraline, venlafaxine.
3. Monoamine oxidase (MAO) inhibitors— Acute toxicity is manifested by (mimic symptoms
Phenelzine, tranylcypromine. of atropine poisoning) delirium, excitement,
4. Atypical antidepressants—Trazodone, nefazo- hypotension, convulsions, fever, arrhythmias,
done, bupropion, mianserine. respiratory depression and coma.
Buspirone is an azapirone with good anxiolytic reduced. They have a low safety margin and may
properties. It is a selective 5-HT1A partial agonist produce convulsions.
and a weak D2 antagonist. It is useful in mild to
moderate anxiety. Antianxiety effect develops Doxapram: It appears to act mainly on the
slowly over 2 weeks. Unlike diazepam, it is not a brainstem and spinal cord and increase the
muscle relaxant, not an anticonvulsant, does not activity of respiratory and vasomotor centers.
produce significant sedation, tolerance or Adverse effects are nausea, cough, restlessness,
dependence and is not useful in panic attacks. hypertension, tachycardia, arrhythmias and
Buspirone is rapidly absorbed and metabo- convulsions.
lized in the liver.
Uses
Dose: 5-15 mg OD or TDS.
1. Doxapram is occasionally used IV as an
Side effects are mild including headache,
analeptic in acute respiratory failure.
dizziness, nausea and rarely restlessness.
2. Apnea in premature infants not responding
β-blockers (page 48) In patients with prominent to theophylline.
autonomic symptoms of anxiety like tremors,
palpitation and hypertension, propranolol may Nikethamide is not used because of the risk of
be useful. β-blockers are also useful in anxiety convulsions.
inducing states like public speaking and stage Psychomotor stimulants: Amphetamine and
performance. They can be used as adjuvants to
dextroamphetamine are sympathomimetic drugs
benzodiazepines.
(Chapter 2).
Meprobamate has anxiolytic property but is not
Cocaine is a CNS stimulant, produces euphoria
preferred now as it is less effective and causes
and is a drug of abuse. It is also a local anesthetic
high sedation.
(page 101).
Hydroxyzine is an antihistaminic with anxioly-
tic actions. But due to high sedation it is not Methylxanthines: Caffeine, theophylline and
preferred. theobromine are the naturally occurring xanthine
alkaloids. The beverages—coffee contains caffeine;
tea contains theophylline and caffeine; cocoa has
CNS STIMULANTS
caffeine and theobromine. Caffeine and theo-
Drugs that have a predominantly stimulant effect phylline are CNS stimulants. They bring about
on the CNS may be broadly divided into: an increase in mental alertness, a reduction of
1. Respiratory stimulants: Doxapram, niketha- fatigue produce a sense of well being and improve
mide. motor activity and performance, with a clearer
2. Psychomotor stimulants: Amphetamine, cocaine flow of thought. Caffeine stimulates the respi-
and methylxanthines. ratory center. Higher doses produce irritability,
3. Convulsants: Leptazol, strychnine. nervousness, restlessness, insomnia, excitement,
and headache. High doses can result in
Respiratory stimulants are also called convulsions.
analeptics. These drugs stimulate respiration and
are sometimes used to treat respiratory failure. CVS: Methylxanthines increase the force of
Though they may bring about temporary contraction of the myocardium and increase the
improvement in respiration, the mortality is not heart rate and therefore increase the cardiac output.
146 Pharmacology for Physiotherapy
Autacoids are substances formed in various inactive form. Histamine found in brain serves as
tissues, have complex physiologic and pathologic a neurotransmitter. Degranulation of the mast
actions and act locally at the site of synthesis. They cells release histamine which is quickly degraded
have a brief action and are destroyed locally. at the site.
Hence they are called local hormones and differ
from true hormones which are produced by Mechanism of Action
specific cells and reach their target tissues through Histamine produces its effects by acting on the
circulation. The word autacoid is derived from histamine receptors. Three subtypes are known.
Greek: autos-self akos-remedy. Histamine, 5- • H1—present in lungs, gut, blood vessels, nerve
hydroxytryptamine (serotonin), endogenous endings and brain.
peptides like bradykinin and angiotensin; • H2—stomach (gastric glands), heart, blood
prostaglandins and leukotrienes are autacoids. vessels and brain.
• H3—CNS.
HISTAMINE AND ANTIHISTAMINES
Actions
HISTAMINE
1. CVS: Histamine dilates small blood vessels
Histamine (tissue amine) (Histos = tissue) is a resulting in hypotension accompanied by
biogenic amine formed in many tissues. It is also reflex tachycardia. Cerebral blood vessels
found in the venoms of bees, wasps and other dilate—producing severe throbbing head-
stinging secretions. ache.
Synthesis, storage, distribution and degradation Triple response: Intradermal injection of
In humans, histamine is formed from the amino histamine elicits triple response comprising
acid histidine. Large amounts are found in the of:
lungs, skin and intestines. Histamine is stored in i. Red spot at the site (flush)—due to local
the granules of the mast cells and basophils in an capillary dilation.
148 Pharmacology for Physiotherapy
Some autacoids with examples of agonists and antagonists. Receptor types are given in brackets
ii. Flare—redness surrounding the ‘flush’ due Adverse reactions include hypotension,
to arteriolar dilatation. flushing, tachycardia, headache, wheal, broncho-
iii. Wheal—local edema due to the escape of fluid spasm and diarrhea.
from the capillaries.
This response is accompanied by pain and Uses
itching. Histamine is of no therapeutic value. It is
2. Smooth muscle: Histamine causes contrac- occasionally used in some diagnostic tests like to
tion of the nonvascular smooth muscles. Thus test the acid secreting ability of the stomach,
bronchospasm and increased intestinal moti- diagnosis of pheochromocytoma, and to test for
lity are produced. bronchial hyperreactivity.
3. Glands: Histamine is a powerful stimulant of Histamine Substitutes
the gastric acid secretion-acts through H2
Betazole is a H2 agonist and can be used in gastric
receptors (Chapter 9). It also stimulates pepsin
function tests. Betahistine is a H1 agonist used to
and intrinsic factor secretion.
control vertigo in Meniere’s disease.
4. CNS: Histamine functions as a neuro-
transmitter in the CNS. ANTIHISTAMINES
5. Nerve endings: Histamine stimulates sensory Histamine antagonists can be H1 receptor blockers
nerve endings causing pain and itching. and H2 receptor blockers.
Autacoids 149
metabolized in the liver and are excreted in the 4. Antiemetic: Promethazine is used to prevent
urine. Route of administration and preparations drug induced and postoperative vomiting. It
are given in Table 7.1. has also been used in ‘morning sickness.’
5. Preanesthetic medication: For its sedative,
Adverse reactions are mild and on continued
anticholinergic and antiemetic properties,
use tolerance develops.
promethazine has been used as preanesthetic
Sedation, dizziness, motor incoordination,
medication.
inability to concentrate make driving dangerous
6. Hypnotic: The sedative antihistamines are
while on antihistamines. Anticholinergic effects
sometimes used to induce sleep. Hydroxizine
like dryness of mouth, blurred vision, constipa-
has been used as an anxiolytic.
tion and urinary retention may be troublesome.
7. Parkinsonism: Some of them are useful in drug
Epigastric distress and headache can also occur.
induced parkinsonism due to their anti-
Many of them are teratogenic.
cholinergic action.
Newer non-sedative antihistamines also called 8. Cough due to postnasal drip can be controlled
second generation antihistamines have the by antihistamines like diphenhydramine.
following advantages over classical antihista-
mines: 5-HYDROXYTRYPTAMINE, ERGOT
• No sedation because they poorly cross the
ALKALOIDS, ANGIOTENSIN AND KININS
blood-brain barrier.
• No anticholinergic side effects as these are
5-HYDROXYTRYPTAMINE
pure H1 blockers and do not block cholinergic
receptors. 5-Hydroxytryptamine (serotonin) is of great
• Some of them like astemizole are long-acting. pharmacological interest. It is found in various
However, the therapeutic indications of these plant and animal tissues. In human body, 5-HT is
agents are limited to allergic disorders like allergic present in the intestines, platelets and brain. It is
rhinitis and chronic urticaria. They are more synthesized from the amino acid tryptophan and
expensive. Terfenadine can very rarely cause fatal stored in granules. It is degraded mainly by
ventricular arrhythmias; erythromycin and monoamine oxidase (MAO).
ketoconazole potentiate this cardiotoxicity.
5-HT Receptors: The actions of serotonin are
Uses mediated through its receptors. Seven types of 5-
HT receptors (5-HT1-7) with further subtypes of 5-
1. Allergic reactions: Antihistamines are useful for
HT1 and 5-HT2 receptors are presently known.
the prevention and treatment of symptoms of
Many receptor selective agonists and antagonists
allergic reactions. They are effective in allergic
are being developed.
rhinitis, conjunctivitis, hay fever, urticaria,
pruritus, some allergic skin rashes and
Actions
pollinosis.
2. Common cold: Antihistamines reduce 1. CVS: The action on blood vessels is complex.
rhinorrhea and afford symptomatic relief in Large vessels are constricted while arterioles
common cold. dilate. A characteristic triphasic response is
3. Motion sickness: Given 30-60 minutes before seen on blood pressure following IV injection.
journey, antihistamines prevent motion Initial fall in BP in followed by a rise and
sickness. They are also useful in treating then fall.
vertigo of Meniere’s disease and other vesti- 2. GI tract: 5-HT increases gastrointestinal
bular disturbances. Cinnarizine is preferred. motility and contraction resulting in diarrhea.
Autacoids 151
Uses Actions
1. Gynecological and obstetrical Leukotrienes cause vasoconstriction, increase
a. Abortion For I and II trimester abortion and vascular permeability leading to edema, increase
ripening of cervix during abortion, PGE2 airway mucous secretion and are potent
154 Pharmacology for Physiotherapy
Others
Adrenaline, ephedrine and isoprenaline are
nonselective β receptor stimulants. Though
adrenaline and isoprenaline produce prompt
bronchodilation, they are not preferred due to the
risk of adverse effects.
Ephedrine produces bronchodilation but is
slow in onset. Because of low efficacy, side effects
and availability of better drugs, ephedrine is not
preferred.
Methylxanthines (page 145)
Theophylline and its derivatives like aminophylline
are good bronchodilators.
Fig. 8.1: Immediate and late responses of Mechanism of action: Phosphodiesterase (PDE)
mast cell activation by antigen is the enzyme that degrades cyclic AMP.
Methylxanthines inhibit PDE and thereby
enhance cAMP levels which brings about
bronchodilation. cAMP also inhibits the release
acting bronchodilators with peak effect in 10 of mediators of inflammation.
minutes. The action lasts for 6 hours. Adverse
effects to β2 agonists include muscle tremors, cAMP
palpitation and nervousness. ↓ PDE ← Methylxanthines
Selective β2 agonists are the most commonly 5’AMP
used bronchodilators as they are the most effective, Aminophylline is given intravenously, slowly
fast-acting, convenient and relatively safe in acute attacks of asthma not responding to β2
bronchodilators. They are available as metered agonists. In an acute attack, drugs given by
dose inhalers, nebulizers and also tablets for oral inhalation may sometimes fail to reach the
use. The proper technique in using the inhaler bronchioles because of severe bronchospasm.
should be taught. ‘Spacers’ can be used in children Intravenous aminophylline may then be tried. 250
and adults who cannot follow the right technique mg aminophylline should be injected slow IV over
of inhalation. 15-20 minutes. Rapid IV injection may cause
Oral β2 agonists have higher adverse effects collapse and death due to hypotension and
and are used only in small children who cannot arrhythmias. Convulsions can also occur and
use inhalers and have occasional wheezing (1-4 should be carefully watched for.
mg 6 hourly).
Adverse effects: Theophylline is a drug of low
Salmeterol is a long-acting selective β2 agonist. therapeutic index. Gastric irritation, vomiting,
The onset of action is slow (hence not useful in insomnia, tremors, diuresis, palpitation, and
Respiratory System 157
hypotension are quite common. Higher doses because of the small dose required. But they are
cause restlessness, delirium, convulsions and not effective in acute attacks and are only of
arrhythmias. Children may develop behavioral prophylactic value. They prevent episodes of acute
abnormalities on prolonged use—should be asthma and bronchial hyperreactivity and
avoided in children. effectively control symptoms. The effect develops
after 1 week of treatment.
Status in bronchial asthma: Theophylline is a
Side effects of inhaled steroids include
second line drug in bronchial asthma.
hoarseness of voice, sore throat and oropharyn-
1. Chronic asthma: Oral theophylline can be used geal candidiasis. Rinsing the mouth and throat
to control mild to moderate asthma. with water after each use can reduce the incidence
Etophylline + 80% theophylline (Deriphylline) of candidiasis and sore throat. No HPA axis
injections (IM) are used to relieve acute attacks. suppression is seen in the recommended doses.
2. Acute severe asthma (status asthmaticus): Beclomethasone dipropionate, budesonide,
Intravenous aminophylline is tried when flunisolide and triamcinolone are used as inhalers.
sympathomimetics fail to relieve broncho-
Dose: Beclomethasone: BECLATE INHALER 50,
spasm—but are found to be less effective.
100 and 200 μg per metered dose → 1-2 Puffs 3-4
3. Apnea in premature infants. times a day.
Anticholinergics (see Chapter 2)—relax bronchial Use of Glucocorticoids in Asthma
smooth muscles but response is slower than
sympathomimetics. Ipratropium bromide is given 1. Acute exacerbation: A short course (5-7 days) of
by inhalation and its actions are largely limited to oral prednisolone is given in addition to β2
the respiratory tract. It is more effective in chronic agonists.
bronchitis. It is safe and well-tolerated. 2. Chronic asthma: Beclomethasone/Budesonide
inhalation for a long period as prophylaxis.
Uses 3. Status asthmaticus: IV hydrocortisone
hemisuccinate followed by oral prednisolone.
1. As an adjunct to β2 agonists.
2. As a bronchodilator in some cases of chronic MAST CELL STABILIZERS
bronchitis.
Cromolyn sodium (disodium cromoglycate) was
synthesized in 1965.
ANTI-INFLAMMATORY DRUGS
Mechanism of action: Cromolyn inhibits the
Glucocorticoids: Since inflammation is the degranulation of mast cells and thereby inhibits
primary pathology in bronchial asthma, anti- the release of mediators of inflammation. It thus
inflammatory agents afford significant benefit. prevents bronchospasm and inflammation
Mechanism of action: Steroids are not broncho- following exposure to allergens. It is therefore used
dilators. They suppress the inflammatory for prophylaxis. It is not a bronchodilator — hence
response to antigen-antibody reaction and thereby not useful in acute episodes.
reduce mucosal edema and hyperirritability. They Cromolyn sodium is used as an inhaler; it
restore response to β2 agonists if tolerance has takes 2-4 weeks of treatment for the beneficial
developed. Oral prednisolone is commonly used. effects to develop.
Adverse effects are rare. Throat irritation,
Inhaled steroids: The use of inhalational steroids cough and sometimes bronchospasm can occur
largely minimizes the adverse effects of steroids on inhalation due to the fine powder.
158 Pharmacology for Physiotherapy
ANTITUSSIVES
3. Expectorants
1. Central cough Codeine, noscapine, dextro-
Expectorants (Latin—expectorate = to drive from
suppressants methorphan, antihistamines,
the chest) increase the production of respiratory
benzonatate.
tract secretions which cover the irritated mucosa.
2. Pharyngeal Lozenges, cough drops,
As the secretions now become thin and less viscid,
demulcents linctuses
they can be easily coughed out. Expectorants may
3. Expectorants Potassium iodide, guaiphe-
increase the secretions directly or reflexly.
nesin, ammonium chloride,
ipecacuanha Direct stimulants: Volatile oils like eucalyptus oil;
4. Bronchodilators Salbutamol, terbutaline creosotes, alcohol, cidar wood oil—when
5. Mucolytics Bromhexine, ambroxol, administered by inhalation with steam can
acetylcysteine, carbocysteine. increase respiratory secretions.
1. Central Cough Suppressants Reflex expectorants are given orally, they are gastric
irritants and reflexly increase respiratory
Central cough suppressants act by inhibiting secretions.
cough center in the medulla.
Potassium iodide acts both directly and reflexly.
Codeine is a good antitussive with less addiction Ipecacuanha is an emetic. In sub-emetic doses it
liability; nausea, constipation and drowsiness are is used as an expectorant.
common. Dose: 10-15 mg every 6 hours (page 123).
Noscapine is a potent antitussive; no other CNS 4. Bronchodilators
effects are prominent in therapeutic doses. Nausea
Bronchodilators like salbutamol and terbutaline
is the only occasional side effect. Dose: 15-30 mg
relieve cough that is resulting from bronchospasm.
every 6 hours.
The antitussive preparations generally have a
Dextromethorphan and pholcodeine are synthetic combination of a central cough suppressant, an
opioid derivatives with antitussive actions like expectorant, an antihistaminic and sometimes a
codeine but with less side effects. Pholcodeine is bronchodilator and a mucolytic agent.
longer-acting—given twice daily.
Benzonatate is chemically related to the local 5. Mucolytics
anesthetic procaine. It acts on the cough receptors Normally the respiratory mucus is watery. The
in the lungs and also has a central effect. It is given glycoproteins in the mucus are linked by
orally. disulphide bonds to form polymers making it
Antihistamines are useful in cough due to allergy slimy. In respiratory diseases, the glycoproteins
except that due to bronchial asthma. form larger polymers with plasma proteins present
160 Pharmacology for Physiotherapy
in the exudate and the secretions become thick Carbocysteine is similar to acetylcysteine and is
and viscid. Mucolytics liquefy the sputum making used orally.
it less viscid so that it can be easily expectorated.
Pancreatic dornase—deoxyribonucleoprotein is
Bromhexine obtained from the plant Adhatoda a major component of the purulent respiratory tract
vasica is a good mucolytic. It depolymerizes the secretions. Pancreatic dornase is a deoxy-
mucopolysaccharides in the mucus. It is given ribonuclease obtained from the bovine pancreas.
orally (8-16 mg thrice daily). Side effects are It breaks the deoxyribonucleic acid (DNA) into
minor—may cause rhinorrhea. smaller parts thus making the secretions thin and
less viscid. It is administered by inhalation.
Ambroxol is a metabolite of bromhexine with
actions similar to it. Ambroxol may be given orally Pancreatic dornase can cause allergic
by inhalation. It can be used as an alternative to reactions.
bromhexine. Steam inhalation offers an effective and
inexpensive alternative to drugs. In presence of
Acetylcysteine opens disulfide bonds in the
dehydration, just rehydrating the patient is found
mucoproteins of the sputum reducing its visco-
to be beneficial.
sity. It is given by aerosol. Side effects are common
and hence not preferred.
Gastrointestinal
Tract
DRUGS USED IN PEPTIC ULCER 2. Drugs that reduce gastric acid secretion
a. H2 receptor blockers—Cimetidine, rani-
Acid-peptic disease is common in the present days tidine, famotidine, roxatidine, nizatidine.
that are full of tension and anxiety. Peptic ulcer b. Proton pump inhibitors (PPIs)—
results from an imbalance between acid-pepsin Omeprazole, lansoprazole, pantoprazole,
secretion and mucosal defense. The factors that rabeprazole.
protect the mucosa are its ability to secrete mucous, c. Muscarinic antagonists—Pirenzepine.
bicarbonate and prostaglandins. Gastric acid 3. Ulcer protectives: Sucralfate, bismuth com-
secretion is controlled by three pathways—vagus pounds.
(ACh), gastrin and local release of histamine— 4. Other drugs: Carbenoxolone, cisapride,
each acting through its own receptors (Fig. 9.1). prostaglandins.
Histamine acts through H2 receptors on parietal
cells while acetylcholine through M1 muscarinic ANTACIDS
and gastrin through G receptors on the parietal
Antacids are basic substances. Given orally they
cells. These activate H+ K+ ATPase (proton pump)
neutralize the gastric acid and raise the pH of
on the parietal cells resulting in the secretion of
gastric contents. Peptic activity is also reduced
H+ into the gastric lumen. This combines with Cl–
because, pepsin is active only above pH 4.
(drawn from plasma) and HCl is secreted.
Antacids are of 2 types:
1. Systemic Sodium bicarbonate
Classification
2. Nonsystemic Aluminium hydroxide, mag-
1. Drugs that neutralize gastric acid: Antacids— nesium trisilicate, magnesium
MgOH2, Al(OH)3 hydroxide, calcium carbonate.
162 Pharmacology for Physiotherapy
Drug interactions: Antacids form complexes with Famotidine is similar to but more potent than
iron, tetracyclines, digoxin, ranitidine, ranitidine. Headache and rashes can occur.
fluoroquinolones, sulfonamides and antimus-
carinic drugs. To avoid these, antacids should be Roxatidine is similar to ranitidine but is more
taken 2 hours before or 2 hours after other drugs. potent and longer-acting.
H2 receptor blockers: Cimetidine, ranitidine,
famotidine, roxatidine. Uses of H2 Blockers
These drugs bind to H 2 receptors and H2 blockers are used in the treatment of:
competitively inhibit the action of histamine on 1. Peptic uler—H2 blockers bring about rapid
H2 receptors and thereby reduce gastric secretion. relief from pain and ulcers heal in 6-8 weeks
Both volume and acidity of basal, nocturnal and of treatment.
food induced secretion are reduced. They can
2. Gastritis and non ulcer dyspepsia—respond
cause 90 percent reduction in gastric secretion by
to H2 blockers.
a single dose. Gastrin induced HCl secretion and
3. GERD—H2 blockers are alternatives to PPIs.
pepsin is also reduced. Due to these actions,
4. Preanesthetic medication—to reduce gastric
healing of peptic ulcers is faster.
acid secretion and prevent damage to the
Pharmacokinetics: H2 blockers are well-absorbed. respiratory mucosa if aspiration occurs during
Cimetidine acts for 5-8 hours, ranitidine and surgery.
famotidine for 12 hours. 5. Zollinger Ellison syndrome—High doses of
Adverse effects: The H2 blockers are well- H2 blockers are used as alternatives to PPIs.
tolerated with minor side effects like dizziness, Ranitidine is the most preferred. It is given
diarrhea, muscle pain and headache. Because the for 4-8 weeks (300 mg daily) in peptic ulcers. It
H2 receptors do not have any significant functions may be continued for 6 months to prevent
in other tissues except stomach, H2 receptor recurrence.
blockers are fairly selective and thereby safe drugs.
Cimetidine has antiandrogenic actions, it Proton Pump Inhibitors
increases plasma prolactin levels and inhibits
oestrogen metabolism in the liver. On prolonged Omeprazole is the most commonly used proton
use it may result in gynecomastia, impotence and pump (PP) inhibitor.
loss of libido. CNS effects include confusion, Mechanism of action: The parietal cells of the
delirium and hallucinations in the elderly. stomach secrete H+ with the help of an enzyme
Headache, dizziness, rashes and diarrhea can H +K+ ATPase (proton pump) present in the
result. Cimetidine inhibits microsomal enzymes plasma membrane. This is the final step in gastric
and interferes with the metabolism of many drugs.
acid secretion. Proton pump inhibitors specifically
Ranitidine is the preferred H2 blocker as it has inhibit this H+ K+ ATPase enzyme and thereby
several advantages over cimetidine. Ranitidine is inhibit gastric secretion. Omeprazole is a prodrug,
more potent, longer acting, has no antiandrogenic gets activated in the acidic environment of the
effects, no CNS effects as it does not cross BBB stomach and a single dose can totally inhibit
and does not inhibit microsomal enzymes gastric secretion. Acid secretion starts only after
significantly. Only adverse effects are headache new H+K+ATPase enzyme is synthesized. Ulcer
and dizziness. heals rapidly even in resistant cases.
164 Pharmacology for Physiotherapy
induced (e.g. NSAIDs) gastric ulceration. Diarrhea occur on long-term use due to blockade of
and muscle cramps are common. dopamine receptors.
Conditions Drugs
used to prepare the gut for surgery, endoscopy DRUGS USED IN THE
and radiological examination (see page 7). TREATMENT OF DIARRHEA
infection. The pathogen should be identified Super ORS—The content of ORS is modified to
whenever possible and treated accordingly. reduce the frequency and severity of diarrhea.
Amino acids are added which could promote
TABLE 9.4: Composition of oral sodium absorption. However they are expensive
rehydration salt/solution (ORS) and the benefit provided is marginal. Studies have
NaCl– — 3.5 gm
shown that boiled rice powder 40-50 g/L is a good
– and simple glucose supplement. Since the rice also
KCl — 1.5 gm
has some proteins (7%), it is a source of amino
Sodium citrate — 2.9 gm
acids which stimulates the absorption of salt and
Glucose — 20 gm water. The starch content adds to the calories. Rice
To be dissolved in 1 liter of boiled and cooled water is easily available, relatively inexpensive and has
good efficacy—rice based ORS may be preferred
WHO–ORS New Formula particularly in developing countries. Wheat, maize
or potato may be used instead of rice.
Standard ORS has Na+ 90 m M, Cl–80 mM, citrate
10 mM and glucose 110 mM making up a total of Antidiarrheal drugs provide symptomatic relief
310 mosm/L. Extensive research sponsored by and include adsorbents and antimotility drugs.
WHO has shown that ORS with lower osmolality
Adsorbents include kaolin, pectin, chalk and
has improved efficacy with a 30 percent reduction
activated charcoal. These adsorb intestinal toxins
in the incidence of vomiting and stool volume.
and microorganisms by coating them.
WHO and UNICEF have therefore recommended
new modified ORS solution with 245 mosm/L
osmolarity in place of the standard preparation Antimotility Drugs (Table 9.5)
with a decreased concentration of sodium and Codeine an opium alkaloid, stimulates the opioid
glucose. The only disadvantage is that it can cause receptors on the gastrointestinal smooth muscles
hyponatremia in adults suffering from cholera.
to reduce peristalsis. This delays passage of
The contents are as follows: intestinal contents and facilitates absorption of
New formula water. Nausea and vomiting may occur.
NaCl : 2.6 gm
Diphenoxylate is an opioid related to pethidine.
KCl : 1.5 gm
It is given with a small dose of atropine in order to
Trisodium citrate : 2.9 gm
discourage abuse. In therapeutic doses CNS effects
Glucose : 13.5 gm
are not prominent-hence no risk of abuse. It is used
Water : 1L
only in diarrheas. Nausea, drowsiness and
Total osmolarity : 245 mOsm/L
abdominal pain may occur.
Loperamide is an opiate. It has selective action and are useful in some diarrheas. They promote
on GI tract with additional antisecretory action. the growth of saccharolytic flora and alter the gut
CNS effects are negligible. It is less sedating, less pH so that the growth of pathogenic micro
addicting and is the most commonly used organisms is inhibited. They are called
antimotility drug. Its low solubility in water ‘probiotics’ and are found to be useful in reducing
discourages abuse by injection. Loperamide may the incidence of antibiotic induced diarrhea.
cause nausea, vomiting and abdominal cramps. Curds and buttermilk are cheaper alternatives.
Loperamide use has resulted in paralytic ileus Antispasmodics: Atropine derivatives like
and several fatalities are reported in children. propantheline and dicyclomine relax gastro-
Hence loperamide is contraindicated in children intestinal smooth muscles and relieve abdominal
below 4 years of age. colics.
Antimotility drugs are used for symptomatic
treatment of non-infective diarrheas and for Traveller’s diarrhea: Infection is the most
traveller’s diarrhea (as adjuvant). common cause of traveller’s diarrhea and should
be treated with suitable antimicrobials. Oral
rehydration salts and loperamide may also be
Other Drugs
used.
Lactobacillus acidophilus and lactobacillus
sporogenes are available as powders and tablets
Hormones
TABLE 10.1: Hormones secreted by the hypothalamus and anterior pituitary and their chief functions
1. a. Growth hormone releasing hormone (GHRH) Growth hormone (GH) Regulates growth
b. Growth hormone release-inhibiting hormone
(somatostatin) (GHRIH) Inhibits GH release
2. Corticotropin releasing factor (CRF) Corticotrophin (ACTH) Stimulates adrenal cortex to
secrete glucocorticoids,
mineralocorticoids and androgens
3. Thyrotropin–releasing hormone (TRH) Thyroid-stimulating hormone Stimulates release of T3 and T4
(TSH, Thyrotrophin)
4. Gonadotrophin releasing • Follicle stimulating Stimulates growth of ovum and
hormone (GnRH, gonadorelin) hormone (FSH) graafian follicle in the female
• Luteinizing hormone and gametogenesis in the
(LH) or (ICSH) male; stimulates ovulation in
females and regulates
testosterone secretion in males
5. Prolactin–releasing factor Prolactin (PRL) Development of
breast and lactation
6. Prolactin-release inhibiting factor — Inhibits prolactin-release
ANTERIOR PITUITARY HORMONES burns and AIDS. It is liable for abuse in athletes
to promote growth.
Growth hormone (GH) a peptide, stimulates the
growth of all organs except brain and eye. It Corticotrophin (Adrenocorticotrophic hormone,
increases the uptake of amino acids by the tissues, ACTH) controls the synthesis and release of
promotes protein synthesis and positive nitrogen glucocorticoids, mineralocorticoids, and andro-
balance. It causes lipolysis and reduces glucose gens from the adrenal cortex (Fig. 10.1). It is used
uptake by skeletal muscles. It brings about linear in the diagnosis of adrenocortical insufficiency.
growth. These anabolic actions are mediated by
Thyroid-stimulating hormone (TSH, Thyrotro-
somatomedins or insulin-like growth factors (IGF)
pin): Thyrotropin stimulates the production and
produced in the liver.
secretion of thyroid hormones and thus regulates
The secretion of growth hormone is regulated
thyroid function. It is used to increase the uptake
by GHRH and somatostatin (GHRIH).
of radioactive iodine in thyroid carcinoma.
GH deficiency in children results in dwarfism
while excessive production results in gigantism Gonadotrophins: Follicle stimulating hormone
in children and acromegaly in adults. (FSH) and luteinizing hormone (LH)—produced
by the anterior pituitary regulate gonadal function.
Uses They stimulate follicular development in women
and also stimulate ovarian steroidogenesis
• GH deficiency: Replacement therapy with GH
(estrogens and progesterone synthesis). In men
in deficient children brings about normal
they promote spermatogenesis.
growth. It can also be used in GH deficient
adults. Uses ‘Menotropins’ is the combination of FSH
• Other conditions: GH has been tried in chronic and LH obtained from urine of postmenopausal
renal failure and in catabolic states like severe women. It is used in (Table 10.2):
174 Pharmacology for Physiotherapy
HYPOTHALAMIC
Releasing hormones
• TRH
• CRH (CRF)
• GnRH analog—Leuprolide
• PRIH
• MSH-RH
Inhibiting hormones
• PIH
• Somatostatin, (GHRIH)
• MSH-IH
PITUITARY THYROID
Anterior pituitary Hormones Antithyroid drugs
• Growth hormone • T3 Propylthiouracil
Antagonist • T4 Carbimazole
• Octreotide Methimazole
• TSH
Iodides
• ACTH
• FSH I131
• LH
• PL • Calcitonin
• MSH
Posterior pituitary
• Oxytocin
• ADH
PARATHYROID PANCREAS
Insulin
Parathormone Glucagon
ADRENAL GONADS
Cortex
Glucocorticoids Sex hormones Antagonists
• Hydrocortisone • Estrogens – • Tamoxifen
• Prednisolone • Clomiphene
• Beclomethasone • Progestins – • Mifepristone
Mineralocorticoids • Androgens – • Flutamide
• Aldosterone
Sex hormones
Medulla Few examples have been
Adrenaline, noradrenaline given for each group
Hormones 175
TABLE 10.2: Uses of hypothalamic and anterior pituitary hormones and their analogs
Hypothalamic hormone Uses
Sermorelin Diagnosis of GH deficiency
Octreotide Acromegaly, hormone secreting tumors
TRH Diagnosis of thyroid disorders
CRF Diagnostic tests in Cushing’s disease and hypothalamic-pituitary function
GnRH (gonadorelin) Diagnostic tests of hypogonadism
Leuprolide Prostatic cancer, uterine fibroids
Anterior pituitary hormone
Growth hormone GH deficiency, chronic renal failure, burns
Corticotropin Diagnosis of adrenocortical insufficiency
Thyrotropin Test for thyroid functions
Gonadotropins FSH-LH deficiency, undescended testis, amenorrhea, infertility
of the secreted T4 is converted to T3 which is the hyperthyroidism, diffuse goiter and IgG anti-
active hormone. Both T4 and T3 are extensively bodies that activate TSH receptors. Antithyroid
bound to plasma proteins. The free hormone is drugs may act by interfering with the synthesis,
metabolized in the liver and excreted in the bile. release or actions of thyroid hormones.
The t½ of T4 is 6-7 days and that of T3 is 1-2 days.
Drugs used in hyperthyroidism
T3 is 3-5 times more potent than T4 and acts faster.
1. Antithyroid drugs: Thionamides—Propylthiou-
Actions: Thyroid hormones are essential for racil, methimazole, carbimazole.
normal growth, development, function and 2. Iodine: Iodides and radioactive iodine.
maintenance of all body tissues. Congenital Thionamides act by inhibiting the synthesis of
deficiency results in cretinism. Thyroid hormones thyroid hormones. Propylthiouracil also inhibits
have important metabolic functions—they peripheral conversion of T4 to T3. T3 and T4 levels
increase metabolic rate, enhance carbohydrate and fall. Large doses may stimulate release of TSH
protein metabolism and stimulate lipolysis. They resulting in thyroid enlargement. Carbimazole is
facilitate erythropoiesis, are essential for normal commonly used as it is more potent and long-
functioning of the CNS (mental retardation is seen acting. Adverse effects are allergic reactions,
in cretinism), skeletal muscles, cardiovascular jaundice, headache and rarely granulocytopenia.
system, reproductive system and gastrointestinal
system (hypothyroid patients are constipated Uses: Hyperthyroidism—antithyroid drugs are
while hyperthyroid have diarrhea). used in hyperthyroidism.
a. Graves’ disease or diffuse toxic goiter needs long
Uses: Both thyroxine and triiodothyronine term (1-15 yrs) treatment with antithyroid
(leothyronine) are available and are given orally. drugs.
1. Replacement therapy: b. Toxic nodular goiter:—As an alternative—
• In cretinism, treatment should be started when surgery cannot be done as in case of the
immediately to avoid mental retardation. elderly patients.
Replacement should be continued lifelong. c. Preoperatively—Hyperthyroid patients are
• Hypothyroidism in adults can be reversed made euthyroid with antithyroid drugs and
by appropriate treatment. then operated.
• Myxedema coma is a medical emergency. IV Iodides inhibit the release of thyroid hormones
thyroxine or liothyronine should be given and in thyrotoxic patients the symptoms subside
with prophylactic corticosteroids to avoid in 1-2 days. The gland becomes firm, less vascular
adrenal insufficiency. and shrinks in size over a period of 10-14 days.
2. Non-toxic goiter: T4 suppresses TSH production These effects are transient and decrease after 15
and the goiter regresses. days.
3. Thyroid carcinoma: T4 induces temporary
Adverse effects include allergic reactions like
remission. It is used after surgery.
skin rashes, conjunctivitis, swelling of the lips and
4. Miscellaneous: Thyroxine is tried in refractory
salivary glands, fever and lymphadenopathy.
anemias, infertility and non-healing ulcers.
Chronic overdose can cause iodism with metallic
taste, excessive salivation, lacrimation, running
Hyperthyroidism and Antithyroid Drugs
nose, sore throat, cough and rashes.
Hyperthyroidism is due to an excess of circulating
thyroid hormones and could be due to various Uses
causes. Graves’ disease, an autoimmune disorder, 1. Preoperative preparation for thyroidectomy:
is the most common cause. It is characterized by Iodine is started just 10 days prior to surgery
Hormones 177
to make the thyroid gland firm and less metabolism of carbohydrates, lipids and proteins.
vascular. It is a common condition affecting 1-2 percent of
2. Severe thyrotoxicosis: Iodides act rapidly to population and has a strong hereditary tendency.
reduce the release of thyroid hormones. Diabetes mellitus can be of 2 types.
3. Prophylaxis: Iodide or iodate is added to salt
Type I: Insulin dependent diabetes mellitus
used in cooking to prevent endemic goiter.
(IDDM) is an autoimmune disorder where
4. Antiseptic
antibodies destroy the β cells of the islets of
5. Expectorant: Used in cough.
Langerhans. It usually occurs in young children
Radioactive iodine 131I given orally as a solution and adolescents (hence called juvenile onset
is rapidly absorbed and is concentrated by the diabetes mellitus).
thyroid in the follicles. It emits β rays which Type II: Non-insulin dependent diabetes mellitus
penetrate only 0.5 mm to 2 mm of the tissue so (NIDDM) is of maturity onset. Most patients are
that it destroys only the thyroid tissue without obese. There is both reduced sensitivity of tissues
damaging the surrounding structures. to insulin and impaired regulation of insulin
It is used in the treatment of hyperthyroidism secretion.
and in thyroid carcinoma. Small dose is also used
for diagnostic purpose in thyroid function tests. INSULIN
Advantages of 131I are that administration is
simple and convenient; surgery and its associated In 1921 Banting and Best obtained insulin in the
risks can be avoided. The disadvantages are (i) form of pancreatic extract. In 1922 the extract
the long time (3 months) taken for maximum containing insulin was first used on a 14 years
response, and (ii) the risk of hypothyroidism. old boy suffering from severe diabetes mellitus
with excellent response. Insulin was then purified
β-adrenergic blockers: Many of the symptoms in a few years.
of hyperthyroidism are of sympathetic overactivity
as there is increased tissue sensitivity to Chemistry, synthesis and secretion: Natural
catecholamines in hyperthyroidism. β adrenergic insulin is a polypeptide synthesized from the
blockers like propranolol relieve symptoms like precursor proinsulin. Human insulin differs from
palpitation, tremors, nervousness, sweating and bovine insulin by 3 amino acids and from porcine
myopathy. They only afford symptomatic relief insulin by 1 amino acid. Hence porcine insulin is
and are used as adjuvants. closer to human insulin. It is stored in granules in
the β islet cells of the pancreas. Normal pancreas
Ionic inhibitors interfere with the concentration releases about 50 units of insulin everyday. The
of iodine by the thyroid gland. Thiocyanate and secretion is regulated by factors like food,
perchlorate inhibit the organification of iodine but hormones and autonomic nervous system. The
are not used now due to the adverse effects. Ciga- islets of Langerhans are composed of 4 types of
rette smoking, sodium nitroprusside and certain cells—β cells secrete insulin, α(A) cells glucagon,
food items like cabbage increase the concentration δ(D) cells somatostatin and P cells secrete
of thiocyanate in the blood and may result in pancreatic polypeptide.
hypothyroidism. Insulin is metabolized in the liver, kidney and
muscle.
INSULIN AND ORAL HYPOGLYCEMICS
Actions of Insulin
Diabetes mellitus is a chronic metabolic disorder 1. Carbohydrate metabolism: Insulin stimulates
characterized by hyperglycemia and altered the uptake and metabolism of glucose in the
178 Pharmacology for Physiotherapy
Highly purified insulins and human insulin are also available as regular and lente preparations
extracted. This is modified to get human insulin. Insulin delivery devices have been designed which
It can also be obtained by enzymatic treatment of make insulin administration more convenient.
porcine insulin. Human insulin is available as Portable pen injectors are small pen-size devices
regular, NPH, lente and ultralente preparations. containing multiple doses of insulin and
Human insulin is less immunogenic and is retractable needles. They can be carried to the
absorbed more rapidly; dose needed is lesser (10%). place of work and while travelling. Insulin pumps
It is more expensive. deliver appropriate doses of insulin on the basis
Indications for highly purified/human insulins: of self monitored blood glucose results. The set is
1. Allergy to conventional preparations. inserted subcutaneously.
2. Insulin resistance. Alternative routes of insulin delivery have been
3. Lipodystrophy at the site of injection. tried—inhaled insulin and insulin nasal spray
4. Pregnancy. are being evaluated for use.
• Stimulate peripheral uptake of glucose in in the intestines and reduce the absorption of
tissues in the presence of insulin. carbohydrates. They also inhibit the digestion of
Phenformin is not used therapeutically as it carbohydrates. Adverse effects include diarrhea,
causes lactic acidosis. Metformin is safer with flatulence and abdominal distension. They can
lower incidence of lactic acidosis. It does not cause be used with other antidiabetics.
hypoglycemia since it is an euglycemic agent. Newer drugs: Pramlintide (amylin analog) and
exenatide (GLP-1 analog) suppress glucagon
Biguanides
release, delay gastric emptying and suppress
• Have insulin-like effects
• Do not cause hypoglycemia
appetite. Sitagliptin (DDP-4 inhibitor) increases
• Weight reduction—due to anorexia insulin secretion and decreases glucagon levels.
• Nausea, diarrhea, metallic taste are transient They may be used with other antidiabetic drugs.
• Preferred in obese diabetics either alone or with
sulfonylureas Treatment of Diabetes Mellitus
• Contraindicated in renal, hepatic and cardiac The aim of treatment is to keep the blood sugar
diseases. within normal limits and prevent complications
of diabetes. In IDDM, insulin is the only treatment.
Adverse effects: Nausea, diarrhea, and metallic
Mild NIDDM may be controlled by diet, exercise
taste are self-limiting. Rarely lactic acidosis can
and weight reduction. When not controlled, an
occur. Anorexia is advantageous as it helps in
oral hypoglycemic should be given. Most NIDDM
reducing body weight. Long term use may interfere
patients may require insulin sometime later in life.
with vitamin B12 absorption.
Meglitinides Repaglinide and nateglinide Status of oral antidiabetics: Uncomplicated
increase the release of insulin by acting on NIDDM patients not controlled by diet and
pancreatic β-cells. They are well tolerated with exercise are given OAD. Mild NIDDM patients
minor adverse effects like hypersensitivity with recent onset diabetes, age above 40 years at
reactions, hypoglycemia and gastrointestinal the onset of diabetes, obese with fasting blood
disturbances. Meglitinides may be used either sugar < 200 mg/dl are candidates for oral
alone or with biguanides in NIDDM patients. hypoglycemics. They are convenient to use.
Sulfonylureas are preferred, but when blood sugar
Thiazolidinediones (TZDs) increase glucose is not adequately controlled, metformin can be
transport into muscle and adipose tissue and added. Metformin has the advantages of reducing
reduce hepatic glucose output. They may cause appetite and being euglycemic. In conditions like
edema, weight gain and anemia. Liver function stress, surgery or in any of the complications of
should be monitored. TZDs may be used with diabetes, insulin should be used (Table 10.4). In
other antidiabetics. some patients, insulin may be given along with
α -glucosidase inhibitors: Acarbose and sulphonylureas because the latter increase the
miglitol inhibit the enzyme α-glucosidase present tissue sensitivity to insulin.
7. Mental disturbances like euphoria, psychosis proper drug history. If the patient has
or depression can occur with high doses. received long-term steroids within previous
8. Cataract and glaucoma may follow long-term six months, prophylactic hydrocortisone
use of glucocorticoids even as eyedrops. should be administered to avoid shock. Two
9. Delayed wound healing—Steroids may delay weeks of use of > 20 mg hydrocortisone/day
wound healing. needs tapering of the dose.
10. Other effects include raized intracranial In order to minimize HPA axis suppres-
pressure, convulsions, hypercoagulability of sion, (i) lowest effective dose of a glucocorticoid
the blood and menstrual disorders. for the shortest possible period should be used,
11. HPA axis suppression depends on the dose, (ii) the drug should be given in a single
duration and time of administration. After morning dose, (iii) administration on alternate
prolonged steroid therapy, adrenal cortex days is found to be associated with least/no
gradually atrophies due to feedback inhibi- HPA axis suppression and whenever
tion. If steroid administration is suddenly possible this measure should be followed,
especially when long-term steroids are
stopped, acute adrenal insufficiency results.
needed.
Hence after prolonged administration,
12. Mineralocorticoid effects including salt and
steroids should be tapered before withdrawal
water retention, edema, hypokalemia
to allow HPA axis to recover. Prior to surgery and hypertension are rare with selective
or general anesthesia, it is advisable to elicit glucocorticoids.
Hormones 187
ESTROGENS, PROGESTINS
AND ORAL CONTRACEPTIVES
PHYSIOLOGIC CONSIDERATION
At puberty, the ovary begins its cyclic function
called menstrual cycle which stretches over 30-40
years characterized by regular episodes of uterine Fig. 10.4: Regulation of secretion
bleeding. of gonadal hormones
Hormones 189
agonist depending on the site. Raloxifene, Adverse effects include hot flushes, leg cramps
tamoxifen and ormeloxifene have actions similar and an increased risk of deep vein thrombosis
to tamoxifen and are all termed selective estrogen and pulmonary embolism. Raloxifene is indicated
receptor modulators (SERMs). SERMs bind to for the prevention of post-menopausal osteo-
estrogen receptors and have tissue-selective porosis.
estrogenic activities i.e.:
• They have agonistic effects on bone, lipid PROGESTINS
metabolism, brain and liver. Progesterone is the natural progestin synthesized
• Antagonists at breast, pituitary and in the ovary and placenta. It is also synthesized
endometrium. by the testis and adrenals where it acts as a
• Partial agonist at genitourinary epithelium, precursor of various steroid hormones (see under
bone remodeling and cholesterol metabolism. corticosteroids).
Tamoxifen is given orally. Side effects include
hot flushes, nausea, vomiting, vaginal bleeding Progestins
and skin rashes. Natural Progesterone
Tamoxifen is used in advanced breast cancer Synthetic Medroxyprogesterone acetate
in postmenopausal women with estrogen Allylestrenol
receptor-positive tumors. Megestrol
Norethisterone acetate
Clomiphene citrate binds to the estrogen recep-
Lynestrenol
tors and acts as a competitive inhibitor of
Norgestimate
endogenous estrogens. Like tamoxifen, it is also a
partial agonist. Clomiphene opposes the negative
Actions
feedback of endogenous estrogens on the hypo-
thalamopituitary axis resulting in increased 1. Uterus: The secretory changes in the uterine
gonadotropin secretion and thereby induces endometrium like increased tortuosity of the
ovulation. glands are due to progesterone. In pregnancy,
decidual changes in the endometrium take
Side effects include ovarian hyperstimulation place under the influence of progesterone.
resulting in multiple pregnancy, ovarian cysts, Progesterone is very important for the
hot flushes, headache and skin rashes. maintenance of pregnancy (Progestin = favors
Uses pregnancy).
2. Cervix: The watery secretion of the cervix is
1. Infertility: Clomiphene citrate is used to induce
changed to a thick scanty secretion by
ovulation in infertility due to ovarian
progesterone.
disorders.
3. Vagina: Vaginal epithelium changes to that
2. In vitro fertilization: Clomiphene induced
seen in pregnancy by the influence of
ovulation is also useful in in vitro fertilization.
progesterone.
Raloxifene acts as an estrogen receptor agonist 4. Breast: Along with estrogen, progesterone is
in the bone. In women with postmenopausal responsible for the development of the
osteoporosis, raloxifene has antiresorptive effects secretory apparatus in the breast and prepares
on the bone. It reduces bone loss and may even the gland for lactation.
help to gain bone mass. Raloxifene also lowers 5. Body temperature: Increase in the body
LDL. It acts as an estrogen antagonist in the breast temperature by 1°C that is seen during luteal
cancer. Raloxifene does not stimulate the uterine phase which begins at ovulation is due to
endometrial proliferation. progesterone.
Hormones 191
Adverse effects: Headache, breast engorgement, facilitates expulsion of the blastocyst. If given
rise in body temperature, edema, acne and mood during the follicular phase—it also delays
swings may be seen. Progesterone is teratogenic. ovulation.
Mifepristone also binds to glucocorticoid
Uses receptors.
1. Contraception (see below).
2. Hormone replacement therapy (HRT): Progestins Uses
are combined with estrogens in HRT of 1. Termination of pregnancy: Early pregnancy up
postmenopausal women. Estrogen adminis- to 9 weeks can be terminated with a single
tration increases the risk of endometrial oral dose—600 mg of mifepristone followed
cancer—supplementing it with progestin 48 hr later by a prostaglandin to increase
counters this risk. uterine contractions and facilitate expulsion
3. Ovarian suppression: Progestins are used to of the blastocyst.
suppress ovulation in dysmenorrhea, Adverse effects include heavy bleeding,
endometriosis, dysfunctional uterine bleeding nausea and abdominal pain.
(DUB) and premenstrual syndrome. 2. Postcoital contraceptive: Mifepristone prevents
4. Threatened or habitual abortion: Efficacy in such implantation when given within 72 hr after
patients is not proved. coitus.
5. Endometrial carcinoma: Progestins are used as Regular use of mifepristone in late luteal phase
a palliative measure in cases with metastasis. acts as a contraceptive.
Oral contraceptives are also available as lesser side effects reported. Two tablets should be
biphasic or triphasic preparations (Table 10.8). taken within 72 hours of coitus and repeated after
This reduces the amount of hormones needed and 12 hours has an efficacy of 90-98 percent. It is
more closely mimics menstrual cycles. advocated as an emergency method in situations
If a woman misses a pill, she should take 2 following rape or contraceptive failure. It prevents
pills the next day and continue the course. If more implantation.
than 2 pills are missed, then that course should Depot preparations are given as:
be withdrawn, should follow an alternative 1. Intramuscular injections of progesterone at
method of contraception for that particular cycle 3-6 months intervals, e.g. depot medroxy-
and restart the course of oral contraceptives on progesterone acetate (DMPA) (150-400 mg)
the 5th day of the next menstrual cycle. If the or Norethisterone enanthate (NET EN)
woman has conceived, the pregnancy should be (200 mg).
terminated because these hormones are 2. Subcutaneous implants—They are implanted
teratogenic. under the skin.
Mini-pill: A low dose progestin is taken daily Norplant capsules implanted subcutaneously in
without a gap. As estrogen is not used, its adverse the forearm or upper arm work for 5 years.
effects are also eliminated. But efficacy is lower, Disadvantages i. Amenorrhea is frequent.
menstrual cycles may be irregular and is therefore ii. Permanent sterility may occur.
not popular and not preferred.
Mechanism of action of oral contraceptives: The
Postcoital contraceptives: High dose of an combined pill blocks the release of gonado-
estrogen was used earlier. The combined pill is trophins from the pituitary and thereby inhibits
now preferred due to lower doses needed and ovulation.
Stat—at once
Hormones 193
Progestin only preparations make the cervical contraception is desired (The tablet should be
mucus thick and scanty and thereby inhibit sperm continued without withdrawing for menstrua-
penetration. They also inhibit tubal motility and tion).
delay ovum and sperm transport. Centchroman has the following advantages:
1. Success rate claimed is 97-99 percent.
Adverse effects: Headache, nausea, vomiting,
2. It is devoid of the side effects of hormonal
breast tenderness, amenorrhea and irregular
contraceptives.
menstrual cycles may be commonly seen. Weight
3. Long t½ allows once a week administration.
gain, acne, mood swings and hirsutism may
4. No teratogenicity, carcinogenicity or
occur. More severe side effects include—
mutagenicity reported.
cardiovascular effects—in women >35 years there
5. It is well tolerated.
is an increased risk of MI and venous thrombo-
Centchroman may cause prolongation of
embolism.
menstrual cycles in 10 percent of women. It may
Cancers: OCs may increase the incidence of cause ovarian enlargement and should be
cervical, breast and other cancers—but is avoided in polycystic ovaries. It should also be
controversial. avoided in renal and hepatic dysfunction,
Cholestatic jaundice and gallstones: Incidence may tuberculosis and in lactating mothers.
be higher.
ANDROGENS AND ANABOLIC STEROIDS
Contraindications to combined pill
• Thromboembolic and cerebrovascular disease Androgens are produced chiefly in the testis and
• Breast cancers small amounts in the adrenal cortex. In the
• Liver disease females, small amounts of androgens are
• OCs should be used with caution in diabetes, produced in the ovary and adrenal cortex.
hypertension, convulsive disorders, edema and Testosterone is the most important natural
CCF. androgen. In the adult male, 8-10 mg of testo-
sterone is produced daily. Secretion is regulated
Benefits of combined pills by gonadotrophins and GnRH.
1. Effective and convenient method of contra-
Physiological actions: In the male, testosterone
ception.
2. Reduced risk of ovarian and endometrial cancers.
is essential for the development of secondary
3. Reduced incidence of pelvic inflammatory disease sexual characters and sex organs. It is necessary
and ectopic pregnancy. for normal spermatogenesis and is important for
4. Menstrual benefits—loss menstrual blood less, maintaining sexual function in men. Testosterone
less iron-deficiency; premenstrual tension and promotes bone growth, enhances the muscle mass,
dysmenorrhea are less intense. protein synthesis and positive nitrogen balance—
has anabolic actions.
Centchroman a chroman derivative is a Mechanism of action is similar to other steroids.
nonsteroidal oral contraceptive developed by Androgens bind to androgen receptors on the
research institute (CDRI), Lucknow. It has anti- target cells, the complex moves to the nucleus
estrogenic and antiprogestogenic activity and may where it stimulates protein synthesis.
act by preventing implantation. Onset of action is
quick (< 60 minutes) and duration of action is 7 Adverse effects: Masculinization and acne in
days. Dosage (Saheli, Centron) 30 mg twice a week females, hepatotoxicity, increased libido and
for 3 months followed by once a week till precocious puberty can occur in young boys. With
194 Pharmacology for Physiotherapy
large doses, salt and water retention, suppression balance is corrected, appetite improves and
of spermatogenesis resulting in infertility can be there is a feeling of well being.
seen. Feminizing effects like gynecomastia in men 2. Senile osteoporosis: In elderly males respond by
can occur as some androgens are converted to formation of new bone tissue.
estrogens. 3. Growth stimulation in children: Anabolic
steroids promote linear growth in prepubertal
Uses boys. They may be used only for short periods—
but actual benefit on final height is not
1. Testicular failure: Androgen replacement established.
therapy in primary and secondary testicular 4. Other uses: Anabolic steroids are tried in
failure. chronic renal failure to reduce nitrogen load
2. Other uses: Androgens may be used in senile on the kidneys. They may benefit in refractory
osteoporosis and carcinoma of the breast in anemias with bone marrow failure.
premenopausal women. 5. Abuse in athletes: Anabolic steroids enjoy a
reputation for improving athletic performance.
ANABOLIC STEROIDS When combined with adequate exercise, the
muscle mass increases. But the dose used by
Anabolic steroids are synthetic androgens with athletes is very high and is associated with
higher anabolic and low androgenic activity. serious adverse effects like testicular atrophy,
These are believed to enhance protein synthesis sterility and gynecomastia in men and
and increase muscle mass. But with higher doses, virilizing effects in women; increased
the relative anabolic activity is lost and these drugs
aggressiveness, psychotic symptoms and
act like other androgens.
increased risk of coronary heart disease in both
Adverse effects are similar to those caused by sexes. Moreover, there is no evidence that
androgens. athletic performance improves. Hence the use
of anabolic steroids by athletes has been
Preparations of anabolic steroids banned and is medically not recommended.
stuffiness can occur. Sildenafil potentiates the metabolism are calcitonin, growth hormone,
hypotensive action of nitrates and is contra- insulin, thyroid hormone, prolactin, gluco-
indicated in patients on nitrates and in patients corticoids and sex hormones.
with coronary artery disease. Elderly men above
60 years need less dose (25 mg). Patients with liver CALCIUM
disease, kidney disease, bleeding disorders and Calcium is essential for tissue excitability,
elderly people are at a higher risk of toxicity. muscular excitation-contraction coupling, secre-
Several deaths have been reported in such tion from glands, myocardial contractility and
patients. formation of bone and teeth. It also maintains the
Vardenafil has properties similar to sildenafil. integrity of mucous membranes and cell
Dose 5-10 mg. Tadalafil is more potent and longer membrane. Calcium is essential for normal blood
acting than sildenafil. coagulation.
Other drugs used in male sexual dysfunction Calcium is absorbed from the small intestine
are alprostadil a prostaglandin E analog and by a carrier mediated active transport. Normally
papaverine with phentolamine (an α blocker) about 30 percent of the dietary calcium is
injected directly into the cavernosa. absorbed, while in Ca++ deficiency, the absorption
increases under the control of vitamin D (Fig. 10.5).
The normal plasma calcium level is 9-11 mg/dl. It
AGENTS AFFECTING is excreted in feces, urine and sweat.
BONE MINERAL TURNOVER
Some preparations of calcium
Calcium and phosphorus are the most important
Salt Formulation Dose
minerals of the bone with 1-2 kg of calcium and 1
Calcium 10 percent inj—given IV 10-20 ml
kg of phosphorus stored in it. Calcium and
gluconate 500 mg, 1 gm tablets
phosphorus metabolism are chiefly regulated by
vitamin D and parathormone. Other hormones Calcium 5-10 percent solution IV 5-10 ml
that also influence calcium and phosphorus chloride
Adverse effects: Oral calcium can produce calcium absorption from the intestines. PTH also
constipation. promotes phosphate excretion.
Hypoparathyroidism is characterized by low
Uses plasma calcium levels with its associated
manifestations. Hyperparathyroidism which is
1. To prevent and treat calcium deficiency
most commonly due to parathyroid tumor
Calcium supplements are given orally in
produces hypercalcemia and deformities of the
children, pregnant and lactating women and
bone.
in postmenopausal osteoporosis to prevent
PTH is not therapeutically used. It is used for
calcium deficiency.
the diagnosis of pseudohypoparathyroidism.
Tetany: 5-10 ml IV calcium gluconate followed
by 50-100 ml slow IV infusion promptly Hormones that influence bone metabolism
reverses the muscular spasm. The injection
• Vitamin D
produces a sense of warmth. This is followed • Parathormone
by oral calcium 1.5 g daily for several weeks. • Calcitonin
2. Vitamin D deficiency rickets—calcium is given • Glucocorticoids
along with vitamin D. • Estrogens
3. As an antacid—calcium carbonate is used.
4. For placebo effect—IV calcium is used in VITAMIN D
weakness, pruritus and some dermatoses. The
feeling of warmth produced by the injection Vitamin D a fat-soluble vitamin, is a prehormone
could afford psychological benefit. produced in the skin from 7-dehydrocholesterol
under the influence of ultraviolet rays. It is
converted to active metabolites in the body which
PHOSPHATE regulate plasma calcium levels and various
Phosphates play a vital role in various enzymatic functions of the cells.
reactions, are important for the structure and
function of the cells and are important consti- Source
tuents of teeth and bone. Phosphorus is absorbed • Diet—as ergocalciferol (vitamin D 2) from
by the small intestine and excreted through plants.
kidneys under the influence of parathormone. • Cholecalciferol (vitamin D3) is synthesized in
Hypophosphatemia results in muscle the skin from 7-dehydrocholesterol.
weakness and abnormal bone mineralization. Cholecalciferol (vitamin D3) is converted to 25-
OHD3 (calcifediol) in the liver (Fig. 10.6) which is
PARATHYROID HORMONE in turn converted to 1,25-dihydroxycholecalciferol
(Parathormone, PTH) (calcitriol) in the kidneys. Calcitriol is the active
form of vit D while calcifediol is the main
Parathormone is a peptide secreted by the
metabolite in circulation. Convertion of calcifediol
parathyroid gland. Secretion of PTH is regulated
to calcitriol is influenced by PTH and plasma
by plasma Ca++ concentration—low plasma Ca++
phosphate concentration.
stimulates PTH release, while high levels inhibit
secretion (Fig. 10.5). Parathormone maintains
Mechanism of Action
plasma calcium concentration by mobilizing
calcium from the bone, promoting reabsorption of Mechanism of action of vitamin D is similar to
Ca++ from the kidneys and by stimulating the glucocorticoids–it binds to the vitamin D receptors,
synthesis of calcitriol which in turn enhances the drug-receptor complex moves to the nucleus
198 Pharmacology for Physiotherapy
Pharmacokinetics
Given orally, vit D is well-absorbed from the small
intestines in the presence of bile salts. It is
converted to 25-OHD3 in the liver and circulates
in the plasma, bound to a protein and is stored in
the adipose tissue. Vitamin D is also degraded in
the liver and the metabolites are excreted in the
bile.
Preparations
• Calciferol capsules 25000; 50,000 IU.
• Cholecalciferol granules—oral 60,000 IU in Ig;
3,00,000 IU/ml; 6,00,000 IU/ml inj.
• Shark liver oil with vit D—1000 IU/ml, vit A—
6000 IU/ml.
Fig. 10.6: Synthesis and functions of vitamin D
Adverse Reactions
4. Vitamin D dependent rickets: It is due to calcitriol they may also have a direct effect on bone
deficiency (inability to convert calcifediol to remodeling.
calcitriol) and is treated with calcitriol.
5. Senile osteoporosis: Oral vit D supplements with BISPHOSPHONATES
calcium may be tried. (Etidronate, Pamidronate,
6. Hypoparathyroidism: Calcitriol with Ca++ Alendronate, Zoledronate)
supplements are beneficial.
Bisphosphonates are analogs of pyrophosphate;
they inhibit bone resorption. Bisphosphonates get
CALCITONIN incorporated into bone matrix, are imbibed by
Calcitonin is a peptide hormone secreted by the osteoclasts and then incapacitate the osteoclasts
parafollicular ‘C’ cells of the thyroid gland. resulting in reduced bone resorption. They
Secretion is regulated by plasma Ca++ concen- also slow the formation and dissolution of
tration, i.e. high plasma Ca++ stimulates calcitonin hydroxyapatite crystals.
release. Fever, gastritis and hypocalcemia can occur.
Long-term use can lead to osteomalacia due to
inhibition of bone mineralization.
Actions
The chief effects of calcitonin are to lower serum Uses
calcium and phosphate by its actions on the bone 1. Pagets disease of the bone—Bisphosphonates
and kidney. It inhibits osteoclastic bone relieve pain and induce remission.
resorption and in the kidney, it reduces both 2. Osteoporosis—Alendronate and residronate
calcium and phosphate reabsorption. are used with calcium and vitamin D for the
In general the effects are opposite to that of prevention and treatment of osteoporosis in
PTH. Calcitonin is used to control hypercalcemia, men and postmenopausal women.
Paget’s disease, metastatic bone cancer and 3. Hypercalcemia in malignancies—Some
osteoporosis and to increase bone mineral density. malignancies are associated with hyper-
Other hormones that regulate bone turnover are calcemia and some of them may result in severe
glucocorticoids and estrogens. Glucocorticoids hypercalcemia which needs to be treated as
antagonize vitamin D stimulated intestinal an emergency. Intravenous infusion of
calcium absorption and enhance renal Ca ++ palmidronate 60-90 mg over 2-3 hrs (or
excretion. Estrogens reduce bone resorption by zoledronate) along with IV fluids and
PTH and also enhance calcitriol levels. Estrogen frusemide promote excretion of calcium in a
receptors are found in bone which suggests that few hours.
Chemotherapy
• GENERAL CONSIDERATIONS
• SULFONAMIDES
• COTRIMOXAZOLE
• QUINOLONES
• BETA-LACTAM ANTIBIOTICS
• BROAD-SPECTRUM ANTIBIOTICS
• AMINOGLYCOSIDES
• MACROLIDES AND OTHER ANTIBACTERIAL AGENTS
• CHEMOTHERAPY OF URINARY TRACT INFECTIONS
• CHEMOTHERAPY OF TUBERCULOSIS
• CHEMOTHERAPY OF LEPROSY
• ANTIFUNGAL DRUGS
• ANTIVIRAL DRUGS
• CHEMOTHERAPY OF MALARIA
• ANTIAMOEBIC DRUGS
• DRUGS USED IN LEISHMANIASIS AND TRYPANOSOMIASIS
• ANTHELMINTICS
• CANCER CHEMOTHERAPY
• IMMUNOSUPPRESSANTS AND IMMUNOSTIMULANTS
• VACCINES AND ANTISERA
and sleeping sickness. Domagk in 1936 demons- 6. Interfere with metabolic steps—Sulfonamides,
trated that prontosil, a sulfonamide dye is effective sulfones, trimethoprim, pyrimethamine
in some infections. Sir Alexander fleming (antimetabolite action).
discovered penicillin in 1928. It was produced for Antimicrobials may also be classified as:
clinical use in 1941 and this marked the beginning 1. Bacteriostatic drugs—suppress the growth of
of the ‘golden era’ of antibiotics. In the last 60 bacteria. For example, tetracyclines,
years, several powerful antibiotics and their semi- sulfonamides.
synthetic derivatives have been produced. 2. Bactericidal drugs—kill or destroy the
bacteria. For example, Penicillins, amino-
Classification glycosides.
Antibiotics may also be grouped based on their
Based on their mechanisms of action, antimicro-
antibacterial spectrum of activity as:
bials are classified (Fig. 11.1) as drugs that:
1. Narrow spectrum antibiotics—For example,
1. Inhibit cell wall synthesis—Penicillins,
penicillin, aminoglycosides.
cephalosporins, vancomycins, bacitracin,
2. Broad-spectrum antibiotics—For example,
cycloserine.
tetracyclines, chloramphenicol.
2. Damage cell membrane causing leakage of cell
contents—Polymyxins, amphotericin B,
Resistance to Antimicrobial Agents
nystatin.
3. Bind to ribosomes and inhibit protein synthesis Resistance is the unresponsiveness of a
Chloramphenicol, tetracyclines, erythromycin, microorganism to the antimicrobial agent. The
aminoglycosides, clindamycin. resistance may be natural or acquired. When
4. Inhibit DNA gyrase—Fluoroquinolones like resistance is natural the organisms never respond
ciprofloxacin, norfloxacin. to the antimicrobial—may be due to the absence
5. Inhibit DNA function (↓DNA dependant RNA of the particular enzyme or target site affected by
polymerase)—Rifampicin. the drug, e.g. gram-negative bacilli are not
sensitive to PnG. But this type of resistance is The resistance acquired by the bacteria
clinically not a problem as alternate drugs are may result in the following:
available. • Production of enzymes that inactivate the
drug, e.g. β-lactamase by staphylococci;
Acquired resistance: Here, the microbes which
aminoglycoside inactivating enzymes by
were previously sensitive to the antimicrobial
E.coli.
agents become resistant to it. Clinically this poses
• Decreased accumulation of the drug in the
a problem.
bacterium, e.g. resistance to tetracyclines
Bacteria acquire resistance by a change in their
by gram-positive and gram-negative
DNA. Such DNA changes may occur by:
bacteria.
(i) Mutation or (ii) Transfer of genes.
• Altered target for the drug—the binding
Mutation is a genetic change that occurs site may be altered, e.g. binding sites for
spontaneously. In any population of bacteria, a aminoglycosides on the ribosomes may be
few resistant mutants may be present. When the altered.
sensitive organisms are destroyed by the anti- • Altered metabolic pathway—bacteria may
biotic, the resistant mutants freely multiply. produce folic acid by an alternate pathway.
Transfer of genetic material: Many bacteria Cross resistance is the resistance seen among
contain genetic material called plasmids in the chemically related drugs. When a microorganism
cytoplasm which carry genes coding for resis- develops resistance to one drug, it is also resistant
tance. These plasmids are transferred to other to other drugs of the same group, even when not
bacteria and spread resistance (Fig. 11.2). exposed to it, e.g. resistance to one tetracycline
means resistance to all other tetracyclines.
This spread may take place by:
1. Transduction: Plasmid DNA is transferred
Prevention of Resistance to Antimicrobials
through bacteriophage, i.e. virus which infects
bacteria. Development of resistance to drugs can be avoided
2. Transformation: Resistant bacteria may release to some extent by the following measures:
genetic material into the medium which is • Antibiotics should be used only when
taken up by other bacteria. necessary.
3. Conjugation: This is the most important mode • Selection of the correct antibiotic is absolutely
of spread of resistance. The plasmid is important.
transferred from cell to cell by direct contact • Correct dose and duration of treatment should
through a sex pilus or bridge and the process be followed.
is known as conjugation. • Combination of drugs should be used as in
tuberculosis to delay the development of
resistance.
Combination of Antimicrobials
A combination of antimicrobial agents is indicated
in certain specific situations. The combination
serves one of the following purposes.
1. To obtain synergism: Combination of
antibiotics is recommended in conditions like
• Bacterial endocarditis—Penicillin + strepto-
Fig. 11.2: Mechanisms of transfer of resistance mycin is synergistic.
Chemotherapy 203
TABLE 11.1: Choice of antibiotics recommended in the treatment of some common infections
Contd...
Other agents
Mycoplasma Atypical pneumonia Erythromycin Azithromycin
pneumoniae Doxycycline
Rickettsia Typhus fever, Q fever Doxycycline Chloramphenicol
Rocky mountain,
spotted fever
Chlamydia Lymphogranuloma Doxycycline Erythromycin
trachomatis venereum, trachoma Azithromycin
Inclusion conjunctivitis,
urethritis
Chlamydia psittaci Psittacosis, pneumonia Doxycycline, doxycycline Chloramphenicol
Chlamydia Erythromycin, azithromycin
pneumoniae
Pneumocystis carinii Pneumonia Cotrimoxazole Trimethoprim + dapsone
206 Pharmacology for Physiotherapy
Uses
1. Urinary tract infection: Uncomplicated acute
UTI is treated for 7-10 days with cotrimoxa-
zole.
Chronic and recurrent UTI—small doses are
given for prophylaxis.
Bacterial prostatitis—Trimethoprim attains
Fig. 11.4: Sequential blockage high concentration in prostatic fluid.
in folic acid synthesis 2. Respiratory tract infections: Upper and lower
The ratio of ‘trimethoprim : sulfamethoxazole’ respiratory infections including bronchitis,
used is 1 : 5 to attain the right plasma concen- sinusitis and otitis media respond.
tration. Among sulfonamides, sulfamethoxazole 3. Bacterial gastroenteritis due to Shigella and
is chosen since its pharmacokinetic properties E. coli respond to cotrimoxazole.
closely match with that of trimethoprim. 4. Typhoid: Cotrimoxazole is used as an
alternative to fluoroquinolones.
Antibacterial spectrum: Cotrimoxazole is effective 5. Pneumocystis jiroveci infection: Cotrimoxazole
against several gram-positive and gram-negative is used for prophylaxis and treatment (high
organisms like Staph. aureus, streptococci, doses) of Pneumocystis pneumonia in
meningococci, C. diphtheriae, E. coli, Proteus, H. neutropenic and AIDS patients. It also protects
influenzae, Salmonella and Shigella. Cotrimoxazole against infection with other gram-negative
also has good efficacy in Pneumocystis jiroveci bacteria.
infections. 6. Chancroid: Cotrimoxazole is the drug of choice.
208 Pharmacology for Physiotherapy
1. Respiratory tract infections like bronchitis, Ureidopenicillins: These are effective against
sinusitis and otitis media respond to Pseudomonas and Klebsiella infections.
ampicillin.
2. Urinary tract infections: Though ampicillin was Beta-lactamase inhibitors: β-lactamases
the drug of choice earlier, many organisms are enzymes produced by bacteria that open up
have now become resistant. the β-lactam ring and inactivate the β-lactam
3. Meningitis: Ampicillin is given with a antibiotics. β-lactamase inhibitors bind to and
cephalosporin. inactivate β-lactamases preventing the destruction
4. Typhoid: Ampicillin is an alternative to of the β-lactam antibiotics. Examples are
ciprofloxacin. clavulanic acid, sulbactam and tazobactam.
5. Septicemia due to gram-negative organisms: Clavulanic acid is combined with amoxicillin
Ampicillin may be used, with an amino- for both oral and parenteral administration. It
glycoside. extends the antibacterial spectrum of amoxicillin.
The combination is used for mixed nosocomial
Bacampicillin: It is an ester of ampicillin. It is infections.
a prodrug that is better absorbed (hence Sulbactam is combined with ampicillin. It is
diarrhea is less common) and longer-acting than given parenterally for mixed pelvic and other
ampicillin. infections. Tazobactam is combined with
Amoxicillin: It is used in similar infections as piperacillin.
ampicillin like respiratory infections, Salmonella
gastroenteritis and urinary tract infection. CEPHALOSPORINS
Amoxicillin is a component of the various
regimens to eradicate H. pylori. Amoxicillin is Cephalosporins are semisynthetic antibiotics with
preferred over ampicillin by many. a beta-lactam ring related to penicillins. They are
derived from cephalosporin-C and have a wider
Amoxicillin differs from ampicillin in the spectrum of activity than penicillins (Table 11.4).
following:
1. Amoxicillin is better absorbed orally.
Mechanism of Action
2. Food does not interfere with its absorption.
3. Diarrhea is rare. Cephalosporins inhibit the bacterial cell wall
4. Given thrice daily. synthesis similar to penicillins.
Chemotherapy 213
Monobactams are monocyclic beta lactams, i.e. pestis and many anaerobes. They also inhibit
they contain a single ring—the beta-lactam ring. rickettsiae, chlamydiae, Mycoplasma, Actinomyces,
E. histolytica and Plasmodia. Many organisms have
Aztreonam is the monobactam available. It is now become resistant.
active against gram-negative bacilli including
Pseudomonas aerugenosa but is not effective against Pharmacokinetics
gram-positive organisms and anaerobes.
Aztreonam acts by inhibiting cell wall synthesis Older tetracyclines are incompletely absorbed
like penicillins. It is given parenterally. from the gut; food interferes with their absorption.
Aztreonam can be used in patients allergic to Doxycycline and minocycline are 100 percent
penicillins as there is no cross allergenicity with absorbed and food does not affect the absorption
other β-lactams . The only reported adverse effects of these two agents. Tetracyclines chelate calcium
are occasional skin rashes. Aztreonam is used in and other metals which reduce their absorption.
Pseudomonas infections especially nosocomial and Hence tetracyclines should not be given with milk,
in other gram-negative infections. iron preparations and antacids.
Tetracyclines except doxycycline and
minocycline are excreted through kidneys. Doxy-
BROAD-SPECTRUM ANTIBIOTICS cycline and minocycline are excreted through gut
and are therefore safe in patients with renal
TETRACYCLINES insufficiency.
Tetracyclines are antibiotics with four cyclic rings
(hence the name) obtained from the soil Adverse Effects
actinomycetes. In addition to gram-positive and 1. GIT: Gastrointestinal irritation, nausea,
gram-negative bacteria, tetracyclines also inhibit vomiting and diarrhea—tetracyclines are to
the growth of other microorganisms like be given with food to minimize these effects.
Rickettsiae, Chlamydiae, Mycoplasma and some 2. Hepatotoxicity may result in jaundice. Acute
protozoa. Therefore, they are called broad- hepatic necrosis may occur in pregnant
spectrum antibiotics. women but is rare.
Tetracyclines Semisynthetic tetracyclines 3. Renal toxicity: Renal failure may be aggravated.
Outdated tetracyclines cause a syndrome like
Chlortetracyline Demeclocycline
Fanconi’s syndrome with vomiting, polyuria,
Tetracycline Methacycline
proteinuria, glycosuria and acidosis due to
Oxytetracycline Doxycycline
metabolites of the outdated tetracyclines.
Minocycline
4. Phototoxicity: Skin reactions and dermatitis on
exposure to sun are more likely with
Mechanism of Action doxycycline and demeclocycline.
Tetracyclines are bacteriostatic. They bind to 30S 5. Effect on teeth and bones: Tetracyclines chelate
ribosomes and inhibit protein synthesis. calcium. The calcium-tetracycline-orthophas-
phate complexes get deposited in the develop-
ing teeth and bones. The deformities depend
Antibacterial Spectrum
on the time of tetracycline administration.
Antibacterial spectrum is broad including gram- Brownish discoloration and pigmentation of
positive and gram-negative organisms like the teeth occur. The growth of skeleton is also
Streptococci, Staphylococci, Gonococci, Meningococci, depressed when given up to 8 years of age.
H. influenza, Brucella, V. cholerae, Campylobacter, Y. Hence tetracyclines are teratogenic.
216 Pharmacology for Physiotherapy
Tigecycline (Tigilcycline)
Adverse Reactions
Tigecycline is a derivative of minocycline.
1. Gastrointestinal disturbances: Nausea, vomiting,
Tigecycline is effective against many gram-positive
diarrhea.
and gram-negative aerobes and anaerobes that
2. Bone marrow depression: Chloramphenicol may
are resistant to tetracyclines including methicillin
cause bone marrow depression by an
resistant staphylococci, vancomycin resistant
idiosyncratic response—resulting in aplastic
enterococci and S. pneumoniae. It is given
anemia which may be fatal. It may be due to a
intravenously in the dose of 50 mg twice daily. It
toxic metabolite.
has a long t½ of 36 hours. Tigecycline is excreted
3. Gray baby syndrome: Newborn babies given through the gut. It is well-tolerated with occasional
high doses of chloramphenicol may develop nausea and vomiting apart from other adverse
vomiting, refusal of feeds, hypotonia, effects of tetracyclines. Tigecycline is useful in life-
hypothermia, abdominal distension and threatening infections.
ashen gray cyanosis—described as ‘gray baby
syndrome’. It may be fatal. Because the AMINOGLYCOSIDES
newborn cannot metabolize and excrete
chloramphenicol adequately, toxicity results. Aminoglycosides are antibiotics with amino
4. Hypersensitivity reactions like rashes and fever sugars in glycosidic linkages. They are derived
are uncommon. from the soil actinomycetes. Aminoglycosides
5. Superinfection can occur. are streptomycin, gentamicin, kanamycin,
tobramycin, amikacin, neomycin and netilmicin.
Drug Interactions
Common Properties of Aminoglycosides
Chloramphenicol inhibits hepatic microsomal
1. Aminoglycosides are not absorbed orally,
enzymes and thereby prolongs the duration of
remain extracellularly and penetration into
action of drugs metabolized by this system. This
CSF is very poor.
may result in toxicity of some drugs like phenytoin,
2. They are all bactericidal.
tolbutamide and dicumarol.
3. They act by inhibiting bacterial protein
synthesis.
Uses
4. They are mainly effective against gram-
Because of the risk of bone marrow toxicity and negative organisms.
availability of safer drugs, chloramphenicol is not 5. They produce variable degrees of ototoxicity
generally preferred. The indications are: and nephrotoxicity as adverse effects.
1. Typhoid fever: Very effective in typhoid. 6. They are excreted unchanged by the kidneys.
218 Pharmacology for Physiotherapy
colistin from Bacillus colistinus are effective against Adverse effects include myalgia and pain at the
gram-negative bacteria. site of injection. The combination is used in the
Mechanism of action: Polymyxin and colistin alter treatment of serious infections due to streptococci
the permeability of the cell membrane resulting in and methicillin-resistant staphylococci.
leakage of the cell contents. They are bactericidal. Linezolid is a recently developed antimicrobial
Polypeptide antibiotics are not absorbed effective against gram-positive anaerobic
orally; applied topically, they may rarely cause organisms. It acts by inhibiting protein synthesis.
skin rashes. It is orally effective. Linezolid is useful in the
Uses treatment of nosocomial infections resistant to
1. Used topically for skin infections, ear and eye other drugs.
infections.
Daptomycin is a lipopeptide obtained from
2. Oral colistin is used in children for diarrhea
Streptomyces roseosporus. Though the exact
due to gram-negative bacilli.
mechanism of action is not known, daptomycin
Others appears to have a unique mechanism of action. It
binds to the cell membrane and depolarizes it.
Bacitracin produced by Bacillus subtilis is effective This leads to outward movement of potassium
against gram-positive bacteria. It inhibits the cell ions resulting in rapid cell death. Daptomycin is
wall synthesis and is bactericidal. It is too toxic to thus bactericidal. It is synergistic with gentamicin.
be given systemically and is therefore used only Antibacterial spectrum—It is effective against
for topical application—in skin infections, aerobic gram-positive microorganisms including
surgical wounds, ulcers and ocular infections methicillin and vancomycin resistant
(Neosporin powder is bacitracin + neomycin). staphylococci and also against anaerobes.
Spectinomycin is related to aminoglycosides and Daptomycin can cause myopathy. It should
is effective against gram-negative bacteria. It can not be used to prevent pneumonia because
be used only in gonorrhea. surfactant in the lungs antagonizes the effects of
daptomycin.
Sodium fusidate (fusidic acid) is effective Daptomycin is used in complicated skin and
against gram-positive organisms particularly soft tissue infections. It may be used as an
staphylococci. It is bactericidal. It is mainly used alternative to vancomycin.
topically as a 2 percent ointment (Fucidin). It may
be given orally for resistant staphylococcal
CHEMOTHERAPY OF
infections.
URINARY TRACT INFECTIONS
Mupirocin is bactericidal against gram-positive
and some gram-negative organisms. It is used as Infection of the urinary tract is quite common and
an ointment (Bactroban) for skin infections. may be acute or chronic. Urinary antiseptics are
drugs which exert antibacterial activity only in
NEWER AGENTS the urinary tract (and no systemic activity). They
include nitrofurantoin and methenamine
Streptogramins—A combination of quinupristin mandelate.
and dalfopristin in the ratio 30:70 is bactericidal
against gram-positive cocci including methicillin- Nitrofurantoin is effective against many gram-
resistant staphylococci. Streptogramins are given positive and gram-negative bacteria. It attains
intravenously; they are rapidly metabolized and high concentration in urine and is used in acute
excreted largely through feces. Hence adjustment UTI, long-term suppression of chronic UTI and
of dose is not required in renal insufficiency. for prophylaxis of UTI.
Chemotherapy 223
Methenamine mandelate—a salt of mandelic Isoniazid (INH) is the most effective and cheapest
acid and methenamine, releases formaldehyde in primary antitubercular drug. It is tuberculocidal
acidic urine below pH 5.5. Formaldehyde is for rapidly multiplying bacilli but static for resting
bactericidal and resistance does not develop to it. bacilli. INH destroys: (i) intracellular bacilli as it
It is used orally in chronic UTI that is resistant to penetrates into the cells, i.e. tubercle bacilli in the
other drugs. macrophages, and (ii) bacilli multiplying in the
Other drugs used in UTI are sulfonamides, walls of the cavities. Thus it is effective against
cotrimoxazole, nalidixic acid, fluoroquinolones, both intra- and extracellular organisms. If used
ampicillin, cloxacillin, carbenicillin, amino- alone, mycobacteria develop resistance to it. Hence
glycosides, tetracyclines and cephalosporins. it should be used in combination with other drugs.
Urinary analgesic—phenazopyridine has Mechanism of action: INH inhibits the synthesis
analgesic actions on the urinary tract and relieves of mycolic acids which is an important component
burning symptoms of dysuria and urgency. of the mycobacterial cell wall.
mycobacteria. It also inhibits most gram-positive Streptomycin (page 218) is tuberculocidal, acts
and gram-negative bacteria like Staph. aureus, N. only against extracellular organisms due to poor
meningitidis, E.coli, Proteus and Pseudomonas. penetrating power. It has to be given IM. When
used alone resistance develops. Because of these
Antitubercular action: Rifampicin is highly disadvantages and its toxicity (oto and
effective, tuberculocidal and is the only drug that nephrotoxicity), streptomycin is not preferred
acts on persisters; acts on both intra- and now.
extracellular organisms and is effective against
tubercle bacilli resistant to other drugs. If used Ethambutol is tuberculostatic and acts on fast
alone resistance develops. multiplying bacilli in the cavities. It is also effective
against atypical mycobacteria. It inhibits the
Mechanism of action: Rifampicin binds to DNA incorporation of mycolic acids into the
dependent RNA polymerase and inhibits RNA mycobacterial cell wall.
synthesis in bacteria. Optic neuritis resulting in decreased visual
acuity and inability to differentiate red from green
Pharmacokinetics: Rifampicin is well-absorbed
is an important adverse effect which needs
and has good tissue penetrability—reaches
stopping of the drug. Other adverse effects include
caseous material, cavities and CSF. It is a
nausea, anorexia, headache, fever and allergic
microsomal enzyme inducer.
reactions.
Adverse effects: Rifampicin is well-tolerated. Skin Thiacetazone is tuberculostatic with low efficacy;
rashes, diarrhea, nephritis and hepatotoxicity can it delays the development of resistance to other
occur. In intermittent dosing regimen, a flu-like drugs and its low cost makes it a suitable drug in
syndrome can occur. combination regimens. Hepatotoxicity, dermatitis,
The urine turns orange yellow color. allergic reactions and GI side effects may occur.
Ethionamide—This tuberculostatic drug is
Uses
effective against both intra and extracellular
1. Tuberculosis and atypical mycobacterial organisms. It is also effective in atypical myco-
infections. bacteria.
2. Leprosy (see page 226). Anorexia, nausea, vomiting and metallic taste
3. Prophylaxis of H. influenzae meningitis in close in the mouth are the most common adverse effects.
contacts. It can also cause hepatitis, skin rashes and peri-
4. Resistant staphylococcal infections—as an pheral neuritis (needs prophylactic pyridoxine).
alternative. Ethionamide is a secondary agent used only
5. Brucellosis—Rifampicin + doxycycline—drug when primary drugs are ineffective.
of choice. Para-aminosalicylic acid (PAS) related to
6. To eradicate meningococcal carrier state. sulfonamides is tuberculostatic. Gastrointestinal
effects like nausea, anorexia, epigastric pain and
Pyrazinamide is tuberculocidal, and is more
diarrhea make it a poorly tolerated drug. Allergic
active in acidic pH. Mechanism of action is not
reactions and hepatitis are also seen. It is rarely
known. It is effective against intracellular bacilli.
used.
If used alone resistance develops. It is well-
absorbed and reaches good concentration in the
Other Second Line Drugs
CSF. Hepatotoxicity is the most common adverse
effect. Hyperuricemia (due to ↓ excretion of uric Amikacin, kanamycin and capreomycin are
acid), arthralgia, anorexia, vomiting and rashes second line drugs that need parenteral
are the adverse effects. administration. They are oto and nephrotoxic and
Chemotherapy 225
Drugs for Mycobacterium avium complex once monthly. Used in combination with dapsone,
(MAC)—Infection with MAC is more common in it shortens the duration of treatment. Given alone—
HIV patients. The drugs effective are rifabutin, resistance develops.
clarithromycin, azithromycin, fluoroquinolones,
Clofazimine a dye, has weak bactericidal actions
ethambutol, clofazimine, amikacin and ethiona-
against M. leprae. It also has anti-inflammatory
mide. Clarithromycin + ethambutol is the
properties which is useful in suppressing lepra
preferred regimen for MAC infection and needs
reactions. It is used orally in multidrug regimens.
lifelong treatment. Rifabutin is used for
Clofazimine causes reddish-black dis-
prophylaxis.
coloration of the skin specially on the exposed
parts which remains for several months. It can
CHEMOTHERAPY OF LEPROSY also cause dryness of skin, itching and photo-
toxicity.
Leprosy caused by Mycobacterium leprae is a
chronic infectious disease affecting skin, mucous
TREATMENT OF LEPROSY
membranes and nerves. Hansen discovered lepra
bacillus in 1873. For the sake of treatment, leprosy is divided into
In India leprosy is a major public health paucibacillary (non-infectious) and multibacillary
problem affecting millions of people. (infectious) leprosy.
Drugs used in leprosy WHO has recommended a combination of
• Sulfones: Dapsone. drugs in leprosy to:
• Rifampicin. 1. Eliminate persisters.
• Clofazimine. 2. Prevent drug resistance.
• Ethionamide. 3. Reduce the duration of therapy.
Dapsone is diaminodiphenylsulfone (DDS) and
Multidrug regimen
is related to sulfonamides.
Mechanism of action: Like sulfonamides, it Drugs Multibacillary Paucibacillary
leprosy leprosy
inhibits the incorporation of PABA into folic acid.
(for 24 months) (for 6 months)
Actions: Dapsone is leprostatic. Though it inhibits
Rifampicin 600 mg once a month 600 mg once a
the growth of many other bacteria, the dose needed
supervized month supervized
is high and is therefore not used. The lepra
Dapsone 100 mg daily self- 100 mg daily self-
bacillus develops resistance to dapsone on administered administered
prolonged use.
Clofazimine 300 mg once —
Dapsone is completely absorbed on oral monthly supervized
administration and reaches high concentrations 50 mg daily —
in skin. It is metabolized in the liver and excreted self-administered
in bile.
All drugs are given orally
Adverse effects: Dapsone is well-tolerated—
anorexia, nausea and vomiting are common and
Lepra reactions are the acute exacerbations that
allergic reactions can occur. Hepatitis and
occur in leprosy. They are triggered by acute
agranulocytosis can occur. Patients with
infections, stress, anxiety and treatment with
lepromatous leprosy may develop lepra reactions.
dapsone.
Rifampicin is rapidly bactericidal to M. leprae and Type I reactions seen in tuberculoid leprosy is
is highly effective. It can be conveniently given a delayed hypersensitivity reaction to the antigens
Chemotherapy 227
• Oral acyclovir is effective in primary and topically in HSV keratitis (it is too toxic for
recurrent genital and labial herpes. In mild systemic use). Eyelid edema, itching and allergic
cases, topical acyclovir can be tried. In reactions may occur.
recurring genital herpes—oral acyclovir is
Trifluridine is used topically in HSV eye
given for 1 year.
infections.
• HSV encephalitis and other severe HSV
infections—IV acyclovir is the drug of Foscarnet is given intravenously to treat CMV
choice. retinitis as an alternative to ganciclovir.
• HSV keratoconjunctivitis: Acyclovir
Vidarabine was used earlier for HSV and VZV
eyedrops are effective.
infections but is now replaced by acyclovir.
2. Herpes zoster: Acyclovir shortens the duration
of illness.
ANTI-INFLUENZA VIRUS AGENTS
3. Chickenpox: In adults and in immunodeficient
patients, acyclovir reduces duration and Amantadine and rimantadine inhibit the
severity of illness. In children, routine use is replication of influenza A viruses. Generally well-
not recommended. tolerated, nausea, vomiting, diarrhea, dizziness,
insomnia and ankle edema are reported.
Valacyclovir is a prodrug of acyclovir. Famciclovir
Rimantadine is longer-acting and has fewer
is a prodrug of penciclovir—used in HSV and VZV
adverse effects.
infections.
Ganciclovir is effective against herpes viruses Uses
especially cytomegalovirus (CMV). Toxicity
1. Treatment of influenza A during an
includes myelosuppression and gonadal toxicity.
epidemic—reduces duration and severity—
It is used in immunocompromised patients with
dose: 200 mg/day for 5 days.
CMV retinitis.
2. Prophylaxis of influenza A during an
Idoxuridine is effective in DNA viruses. It acts by epidemic especially in high-risk patients. Also
inhibiting viral DNA synthesis. Idoxuridin is used for seasonal prophylaxis in high-risk patients.
Chemotherapy 231
Entry inhibitors—Enfuvirtide blocks the entry forms of P. vivax and P. ovale that produce
of the virus (HIV-1) into the cell. It is given as relapses. Given with a blood schizontocide,
subcutaneous injection–causes local reactions. It they bring about radical cure and eradicate
can also cause allergic reactions. the parasite from the body in these relapsing
Maraviroc selectively binds to a receptor that is malarial infections.
necessary for the entry of the HIV-1 into the CD4+ 4. Gametocidal drugs (Primaquine, chloro-
cells and blocks the entry of the virus into it. It is quine and quinine): These destroy gametocytes
well-tolerated; adverse effects are upper and prevent the transmission of malaria.
respiratory infection, cough, myalgia, arthralgia, Chloroquine is a synthetic 4-aminoquinoline. It
sleep disturbances and diarrhea. is a highly effective blood schizontocide with
Integrase inhibitors—Raltegravir binds activity against all 4 species of plasmodia. It also
integrase, which is an enzyme in the HIV that destroys gametocytes of P. vivax, P. ovale and P.
takes part in replication. It is used in the treatment malaria and completely cures falciparum malaria.
of HIV-1 resistant to other drugs. Patients become afebrile in 24-48 hours.
Chloroquine is safe in pregnancy. It also has
CHEMOTHERAPY OF MALARIA anti-inflammatory properties.
Malaria is caused by protozoa of the genus Mechanism of action is not clear. Chloroquine is
Plasmodium, transmitted through the bite of a a base. It concentrates in acidic food vacuoles of
female Anopheles mosquito. It is a major public the parasite and interferes with the degradation
health problem in most of the developing countries of hemoglobin.
including India.
Lifecycle of the malaria parasite—The bite of Adverse effects: Nausea, vomiting, pruritus,
an infected female anopheles mosquito introduces headache, visual disturbances, insomnia and
the parasite into the bloodstream of man. These skin rashes may occur. Prolonged treatment with
multiply in the liver cells and then in RBCs. Once high doses can cause irreversible retinopathy.
they mature in RBCs, they rupture and cause the High doses can also cause cardiomyopathy and
symptoms of malaria. The male and female sexual psychiatric problems.
forms enter the mosquito when they suck the blood
and undergo sexual cycle in the mosquito. Uses (Table 11.9)
Antimalarial drugs can be classified as: 1. Malaria—Chloroquine is highly effective in the
1. Causal prophylactics (Primaquine, treatment of malaria due to sensitive strains of
all 4 species (600 mg base stat, 300 mg after 6
Pyrimethamine): These destroy the tissue forms
hours and 300 mg for the next 2 days). It is
of the parasite in liver cells and prevent inva-
also used for prophylaxis—300 mg/week.
sion of the erythrocytes. They are also called
2. Extraintestinal amoebiasis (page 235)
}
primary tissue schizontocides.
Chloroquine is
2. Blood schizontocides (suppressives): 3. Rheumatoid arthritis effective in these
(Chloroquine, quinine, melfloquine, halo- 4. Photogenic reactions because of its anti-
fantrine, pyrimethamine, chloroguanide and 5. Lepra reactions inflammatory
artemisinin): Suppressives destroy the property
protozoa in the RBCs and terminate clinical
attacks of malaria. Quinine is an alkaloid obtained from the bark of
3. Tissue schizontocides used to prevent the cinchona tree. It destroys erythrocytic forms
relapse (Primaquine): They act on hepatic of the parasite similar to chloroquine and is use-
Chemotherapy 233
ful as a suppressive. It is also gametocidal (except Uses: Quinine is used in the treatment of resistant
for P. falciparum). falciparum malaria and cerebral malaria and for
Quinine also has mild analgesic and nocturnal muscle cramps.
antipyretic activity; myocardiac depressant and
Mefloquine in a single dose is highly effective
local anesthetic properties. It is a skeletal muscle
against erythrocytic forms of vivax and falciparum
relaxant.
malaria—even the multidrug resistant (MDR)
Adverse effects are high. Quinine is a gastric strains of P. falciparum. It is well-tolerated. Nausea,
irritant and causes nausea, vomiting and vomiting, dizziness, confusion, abdominal pain
epigastric pain. Cinchonism with ringing in the and bradycardia are common.
ears, headache, nausea, visual disturbances and Mefloquine is indicated only in MDR strains
vertigo may be encountered. In quinine poisoning, of falciparum malaria.
hypoglycemia, fever, delirium, confusion, Halofantrine is schizonticidal against erythrocytic
hypotension, cardiac arrhythmias and coma may forms of all Plasmodium species including MDR
develop. Death is due to respiratory arrest. strains of P. falciparum.
234 Pharmacology for Physiotherapy
taste in the mouth are the most frequent. Headache, Diloxanide furoate is directly amoebicidal.
stomatitis, dizziness, insomnia, skin rashes and Flatulence, nausea and occasionally abdominal
rarely peripheral neuropathy can occur. High cramps and rashes can occur. It is used alone in
doses can cause convulsions. asymptomatic cyst passers, mild intestinal
Metronidazole has a disulfiram like effect; on amoebiasis and along with a nitroimidazole—for
alcohol intake, antabuse like reaction can follow. the cure of amoebiasis, because diloxanide
eradicates cysts.
Uses
Chloroquine attains high concentration in the
1. Amoebiasis—Metronidazole is the drug of liver, is directly toxic against trophozoites and is
choice in all forms of amoebiasis in the dose of therefore useful in hepatic amoebiasis. As
400-800 mg TDS for 7-10 days. But it does not chloroquine is completely absorbed from the small
eradicate the cysts. intestines, it is not effective against amoebae in
2. Trichomonas vaginitis—Metronidazole 200 the colon. It is used as an alternative to
TDS for 7 days is the drug of choice. metronidazole in hepatic amoebiasis.
3. Giardiasis—Metronidazole given 200 mg TDS
for 7 days is the treatment of choice. Tetracyclines—The older tetracyclines are not
4. Anaerobic infections—Metronidazole is the well-absorbed and large amounts reach the
drug of choice for anaerobic infections. It is colon—hence these are useful in intestinal
given intravenously for serious anaerobic amoebiasis. They inhibit the intestinal flora and
infections. It is also useful for surgical break the symbiosis between them and the
prophylaxis of abdominal and pelvic amoebae. Tetracyclines are used as adjuvants in
infections. chronic cases.
5. H. pylori infections in peptic ulcer patients can
be treated with a combination of metronida- DRUGS USED IN LEISHMANIASIS
zole, clarithromycin and omeprazole/ AND TRYPANOSOMIASIS
ranitidine.
6. Pseudomembranous colitis due to Clostridium LEISHMANIASIS
difficile—responds to metronidazole.
Leishmaniasis is caused by protozoa of the genus
7. Acute ulcerative gingivitis—As an alternative
Leishmania—kala-azar or visceral leishmanias is
to penicillin G.
caused by Leishmania donavani; oriental sore by
8. Dracunculosis—Metronidazole facilitates
L. tropica and mucocutaneous leishmaniasis by
extraction of the guinea worm.
L. braziliensis. The infection is transmitted by the
Tinidazole is longer-acting and is better tolerated bite of the female sandfly phlebotomus. It is
than metronidazole due to lesser side effects. It endemic in Bihar.
can be given 2 grams once daily for 3 days in Drugs used in leishmaniasis include:
amoebiasis and as a single dose for other
indications. Sodium stibogluconate is an antimony
compound which is effective in kala-azar and in
Secnidazole is longer-acting and can be given
mucocutaneous and cutaneous leishmaniasis.
as a single 2 grams dose for most indications of
Adverse effects include a metallic taste in the
metronidazole.
mouth, nausea, vomiting, diarrhea, headache,
Emetine and dehydroemetine directly affects the myalgia, arthralgia, pain at the injection site,
trophozoites but not the cysts. They can be used bradycardia, skin rashes, hematuria and jaundice.
only in severe amoebiasis but are not preferred Some cases of sudden death due to shock have
due to toxicity. occurred. ECG should be monitored as
236 Pharmacology for Physiotherapy
arrhythmias can occur during the later days of benznidazole. Suramin sodium is the drug of
therapy. choice for early stage of trypanosomiasis but it
does not cross the BBB and therefore cannot be
Meglumine antimonate and ethyl stibamine can
used in later stages of the disease. It is also used
also be used in all forms of leishmaniasis.
for the prophylaxis but pentamidine is preferable.
Pentamidine is effective against Leishmania Suramin is also effective in eradicating adult forms
donovani, trypanosomes, Pneumocystis carinii and of Onchocerca volvulus.
some fungi. Toxicity is high; vomiting, shock and loss of
Adverse effects: Pentamidine liberates hista- consciousness may follow IV injections. Rash,
mine which is responsible for vomiting, diarrhea, neuropathies, hemolytic anemia and agranulo-
flushing, pruritis, rashes, tachycardia and cytosis may also occur.
hypotension apart from pain at the injection site.
Pentamidine is useful in visceral leishmaniasis, Melarsoprol is the preferred drug in later stages
trypanosomiasis and in Pneumocystis carinii of trypanosomiasis which is associated with
infections. encephalitis and meningitis.
Eflornithine is used as an alternative in CNS
Other Drugs trypanosomiasis. Nifurtimox and benznidazole
Amphotericin B (page 227) has been tried in are useful in Chaga’s disease (American
leishmaniasis in the endemic areas where trypanosomiasis).
antimonials may be ineffective.
Ketoconazole inhibits ergosterol synthesis in the ANTHELMINTICS
Leishmania and is effective in cutaneous Worm infestations are more common in the
leishmaniasis. developing countries. It is seen in people with poor
Allopurinol In the Leishmania, allopurinol is hygiene. Anthelmintics are deworming agents. A
converted to a metabolite which inhibits protein vermicidal kills while a vermifuge promotes
synthesis. It may be used along with antimonials. expulsion of worms.
Dose: 300 mg 3-4 times a day for 2-4 weeks. Mebendazole a broad-spectrum anthelmintic
cures roundworm, hookworm, pinworm and
Paramomycin (aminosidine) is an amoebicidal
strongyloides infestations. The eggs and larvae
drug which is also found to be effective in
are also destroyed. It blocks the glucose uptake in
leishmaniasis. It is useful in all forms of
the parasite. It is well-tolerated; nausea,
leishmaniasis. It can be used alone or in combi-
abdominal pain and diarrhea are seen in heavy
nation with antimonials.
infestations.
TRYPANOSOMIASIS Uses: Mebendazole is used in the treatment of
roundworm, hookworm, pinworm, tapeworm,
Trypanosomiasis is caused by protozoa of the
trichuriasis and hydatid disease (Table 11.10). It
genus Trypanosoma. African trypanosomiasis
is of special value in multiple worm infestations.
or sleeping sickness is caused by T. gambiense and
T. rhodesiense while South American trypano- Albendazole a congener of mebendazole, has
somiasis is caused by T. Cruzi. Drugs used in actions similar to mebendazole but is better tolerated
trypanosomiasis are suramin, pentamidine, and is effective in a single dose. Adverse effects are
melarsoprol, eflornithine, nifurtimox and similar to mebendazole but milder.
Chemotherapy 237
Piperazine citrate is effective in roundworm and Adverse effects are mild; anorexia, nausea,
pinworm infestations. It competitively blocks the vomiting, dizziness and headache; an allergic
action of acetylcholine and thereby contractions reaction with itching, rashes and fever due to
in the worms. Flaccid paralysis results and the release of antigens from the dying worms may
worms are expelled. occur. Antihistamines are given with DEC to
minimize these reactions. DEC can be given
Levamisole is effective against roundworms and
during pregnancy.
hookworms and can be used as an alternative
drug in these infestations. It is well-tolerated and
is effective in a single dose. It is also an Uses
immunomodulator. • Filariasis: DEC is the drug of choice (2 mg/kg
Niclosamide is effective against most tapeworms. TDS for 21 days). In 7 days patients are
The segments of the dead tapeworms are partly rendered non-infective to mosquitoes as
digested and in case of T. solium, may result in microfilariae rapidly disappear. But adult
visceral cysticercosis. A purgative may be given 2 worms may need repeated courses.
hours after niclosamide to wash off the worms • Tropical eosinophilia (2 mg/kg TDS for 7 days):
and avoid cysticercosis. Symptoms rapidly disappear.
238 Pharmacology for Physiotherapy
Nitrosoureas are effective in meningeal leukemias Methotrexate toxicity can be largely prevented
and brain tumors because they cross the blood- by administering folinic acid. This folinic acid gets
brain barrier. converted to a form of THF that can be utilized by
the cells.
Dacarbazine is useful in malignant melanoma.
Uses: Methotrexate is curative in choriocarcinoma
ANTIMETABOLITES and is useful in acute leukemias, breast cancer
and soft tissue sarcomas. It is also used in
Methotrexate is a folic acid antagonist. It binds to
rheumatoid arthritis and psoriasis.
dihydrofolate reductase (DHFR) and prevents the
formation of tetrahydrofolate (THF). This THF is 6-Mercaptopurine (6-MP) is converted to a
a coenzyme essential in several reactions in metabolite which inhibits purine synthesis.
protein synthesis. The deficiency results in
inhibition of protein synthesis. Thus rapidly Drug interaction: 6-MP is metabolized by xanthine
multiplying cells are the most affected. oxidase. Allopurinol inhibits xanthine oxidase
and thus prolongs the action of 6-MP.
Dihydrofolate
Uses: 6-MP is used in acute leukemias in children,
DHFR ↓← Methotrexate
choriocarcinoma and some solid tumors.
Tetrahydrofolate
5-Fluorouracil inhibits the synthesis of
thymidylate and thereby inhibits DNA synthesis.
Actions: Cytotoxic actions—methotrexate mainly
It is used in carcinoma of the stomach, colon,
affects bone marrow, skin and gastrointestinal
rectum, breast and ovaries.
mucosa.
It also has immunosuppressant and anti- Cytosine arabinoside is the drug of choice in
inflammatory properties. acute myeloid leukemia in adults.
Chemotherapy 241
Drugs which cause least/no Curable cancers and deprives the malignant cells of asparagine
bone marrow depression • Hodgkin’s disease supplies resulting in inhibition of protein
• Hormones • Choriocarcinoma synthesis. It is used in acute leukemias.
• Vincristine • Burkitt’s lymphoma
• Bleomycin • Testicular tumors General Principles in the Treatment
• L-asparaginase • Wilms’ tumor of Cancers (Table 11.12)
• Cisplatin • Acute leukemias
in children Chemotherapy in cancers is generally palliative
• Ewing’s sarcoma and suppressive. Chemotherapy is just one of the
modes in the treatment of cancer. Other modes
MISCELLANEOUS like radiotherapy and surgery are also employed.
Combination of drugs is preferred for synergistic
Procarbazine is effective orally in Hodgkin’s effect, to reduce adverse effects and to prevent rapid
lymphoma (MOPP regimen component). It development of resistance. Drugs which do not
damages DNA. This may make it carcinogenic. depress bone marrow are useful in combination
Cisplatin gets converted to its active form in the regimens to avoid overlapping of adverse effects.
cell, inhibits DNA synthesis and causes With appropriate treatment, cure can now be
cytotoxicity. It causes ototoxicity, nephrotoxicity, achieved in a few cancers. Maintenance of good
peripheral neuropathy, nausea, vomiting and nutrition, treatment of anemia, protection against
anemia. Anaphylactoid reactions can follow its infections, adequate relief of pain and anxiety and
use. It is relatively less toxic to bone marrow. good emotional support—all go a long way in the
Cisplatin is used in ovarian and testicular tumors appropriate management of this dreaded disease.
and cancers of the head and neck.
IMMUNOSUPPRESSANTS
L-asparaginase—The amino acid asparagine is AND IMMUNOSTIMULANTS
synthesized by normal cells but malignant cells
are unable to synthesize asparaginase and depend Immunosuppressants are drugs which inhibit
on the supply from the host. Asparaginase is an immunity. They may suppress cell mediated or
enzyme that converts asparagine to aspartic acid humural immunity or both. They are:
Bacterial vaccines
BCG Live ID/SC At birth 7 and 14 years In all children
attenuated
Cholera Inactivated SC/IM Adults: two doses Every 6 months People living in
1 month apart endemic areas
Diphtheria Toxoid IM 6, 10,14 weeks 18 months and For all children
Pertussis
Tetanus
} TRIPLE
ANTIGEN
Inactivated
Toxoid
IM
IM
of age
6, 10,14 weeks
of age
6, 10,14 weeks
of age
at 4-6 years
18 months and
at 4-6 years
18 months and
at 4-6 years
For all children
Viral Vaccines
Poliomyelitis Live virus Oral 6, 10 and 18 months; again For all children
(OPV) 14 weeks of age at 4-6 years
Measles, mumps, Live virus SC 12-15 months 11-12 years For all children
rubella (MMR)
(Morupar)
Hepatitis A Inactivated IM 1 dose (2-4 weeks After 6-12 1. Travellers to
virus before travelling months endemic areas
to endemic areas) 2. Homosexual men
3. Persons at
occupational risk
Contd...
Chemotherapy 245
Contd...
Vaccine Type of Route of Primary Booster Indication
agent administration immunisation
Hepatitis B Inactive viral IM At birth, After 5 yrs but 1. For all children
antigen 1 month, not routinely 2. Persons at
6-18 months recommended occupational risk
3. Hemophiliacs
4. Postexposure
prophylaxis
Influenza Inactivated IM One dose Yearly 1. High risk people
virus like elderly,
asthmatics
Rabies Inactivated IM/ID Pre-exposure After 1 year then 1. Postexposure
(Rabtpur) virus 3 doses at days at 2-5 years treatment
0,7 and 21 2. Pre-exposure
Postexposure: prophylaxis in
6 doses persons at risk for
IM 0,3,7,14,30 and 90 contact with
rabies virus
Varicella Live virus SC 2 doses 4-8 weeks -- All children from 18
apart at 18 months months to 13 years
with no history of
varicella infection
Yellow fever Live virus SC 1 dose Every 10 years 1. Travellers to areas
where yellow
fever is seen
2. Laboratory
personnel at risk
of exposure
ID—intradermal, SC—subcutaneous, IM—intramuscular
cancers. Levamisole used in helminthiasis is also Interferons α, and β are mainly used for
found to enhance cell-mediated immunity in antiviral effects while interferon γ is used for its
humans. It has been tried in some cancers. immunomodulating actions.
Interferons are indicated in several tumors
Immunization vaccines are used for active
including malignant melanoma, hairy cell
immunization and antisera are used for passive
leukemia, lymphomas, Kaposi’s sarcoma,
immunization. Both of them impart immunity.
condylomata acuminata and in viral infections.
Interferons
VACCINES AND ANTISERA
Interferons are cytokines with antiviral and
immunomodulatory properties. Recombinant Active immunization is the administration of
interferons α, β and γ are avilable for clinical use. antigen to the host in order to induce antibody
They bind to specific receptors and bring about production. Vaccines are used for active
immune activation and increase host defenses. immunization. Vaccines are suspensions of
There is an increase in the number and activity of microorganisms (dead or live attenuated) which
cytotoxic and helper T cells and killer cells. stimulate the immunological defence of the host
246 Pharmacology for Physiotherapy
by developing antibodies. They impart active horses which are actively immunized against the
immunity, which takes sometime to develop and specific organism. Sensitivity tests should be done
are therefore used prophylactically. The before giving antisera.
antibodies so developed destroy the specific Immunoglobulins (Ig) are human gamma-
microorganism when it enters the body (Table globulins that carry the antibodies—like normal
11.13). human gammaglobulin, tetanus Ig, rabies Ig, anti-
Toxoids—Bacterial exotoxins modified to remove diphtheria Ig and hepatitis-B Ig. Allergic reactions
toxicity but retain antigenicity are toxoids. including serum sickness and anaphylaxis can
occur with antiserum, while it is uncommon with
Passive immunization is imparting immunity Igs.
to a host passively by the transfer of antibodies,
e.g. antisera and immunoglobulins (Ig). This Primary immunization provides primary
affords immediate protection as readymade immunity and is usually given in children, e.g.
antibodies are available. Antisera like tetanus DPT (triple antigen given to infants) (Table 11.14).
antitoxin, gas gangrene antitoxin, diphtheria and Secondary immunization is done to reinforce the
antirabies serum are obtained from serum of primary immunity by giving booster doses.
Geriatric
Pharmacology
• PHARMACOKINETIC CHANGES
• PHARMACODYNAMIC CHANGES
• ADVERSE REACTIONS IN THE ELDERLY
People above the age of ‘65’ years are called the would require multiple drugs with the risk of drug
‘elderly’. Though the age considered is 65 years, interactions.
it is just arbitrary and infact, by 5th decade many In general, elderly are two to three times more
of the age related problems start. In women, it could likely to experience an adverse drug reaction.
be even earlier because, the onset of menopause Elderly are more prone to adverse reactions for
itself may mark the beginning of such health the following reasons.
problems. 1. The pattern of drug use in the elderly – it is
The population of the elderly is constantly estimated that >80 percent of people above 65
increasing and could result in a major change in years suffer from one or more chronic diseases
the population structure. The increase in life and consume 40 percent of all drugs. . Thus
expectancy consequent to better health services elderly tend to have multiple diseases
and growth of medical science have contributed requiring multiple drugs.
to a rise in the number of the elderly. The 2. Altered response to drugs in the elderly.
population of the elderly is expanding. The 3. Different doctors may be treating them and one
population above 85 years of age will also grow may not know the other doctor’s prescription,
bigger. Because women live longer than men, leading to risk of toxicity.
women form a larger percentage of the elderly. 4. Older patients often have visual, auditory and
There are also associated social problems – a large cognitive impairment which could lead to
number of women are widowed and this would errors in drug intake.
add to their health problems. Loneliness, quite 5. Elderly may have financial constraints. They
often financial problems, physiological changes may take only some of the medication or even
including hormonal changes, all contribute to a smaller dose of drugs without knowing their
increasing number of problems in the elderly. importance.
Elderly people take more drugs than younger. 6. Elderly are generally physically weaker
They tend to suffer from multiple diseases and section. They are also psychologically and
248 Pharmacology for Physiotherapy
emotionally helpless and down. These make gastric pH which may affect ionization and
them more susceptible for adverse effects. solubility of the drugs. However these changes
7. Problems of drug education and compliance. may not have significant effects on the absorption
8. Polypharmacy – excessive and unnecessary of drugs. This could be because some of the
use of multiple drugs. It is predicted that by changes counter each other. For example, factors
the year 2030, elderly will account for 21 that decrease absorption, like, decreased blood
percent of the population and consume 40 flow, may be opposed by decreased GI motility
percent of all drugs. This indicates that elderly which allow drugs to remain longer in the gut.
receive disproportionately more drugs than Some drugs have increased bioavailability in the
other age groups. This is understandable elderly. A decrease in first pass metabolism may
because elderly suffer from more diseases. Use increase the bioavailability of drugs like
of over-the-counter drugs is also high in the propranolol, levodopa, nifedipine and morphine.
elderly. Polypharmacy adds to the problems. Absorption of drugs by sublingual route may be
Each drug may result in some adverse effect reduced due to decrease in the blood supply to
and more drugs are given to treat these adverse the oral mucosa. Absorption of drugs may be
drug reactions for eg: antacids are given to treat slower and somewhat less complete in the elderly.
gastritis induced by NSAIDs. Use of multiple There are several age related changes in the gut
drugs can also result in drug interactions. that could influence absorption of drugs.
Polypharmacy would result in decreased
compliance and increased financial burden Distribution
to the patient. Elderly may also seek help from
multiple doctors resulting in polypharmacy. Changes in the body composition due to older
Polypharmacy can be prevented by age can modify drug distribution. Changes such
periodically checking the list of drugs received as decrease in total body water, body weight, lean
by the patients. body mass and plasma protein concentration and
The most common adverse effects to drugs increase in percentage of body fat are common in
seen in the elderly are postural hypotension, the elderly. Depending on the properties of the
fatigue, weakness, depression, confusion, drug, these changes can influence the drug
movement disorders, extrapyramidal symptoms distribution -
and volume depletion. • Drugs that are extensively bound to plasma
proteins will now have more free fraction to
Age related changes: There could be certain act and can produce a greater response
pharmacokinetic and pharmacodynamic changes (because of decreased plasma proteins).
in the elderly which make them more susceptible • Water soluble drugs like morphine will have
to adverse drug effects. a higher concentration in the body because
they are distributed in a smaller volume of
PHARMACOKINETIC CHANGES body water.
• Lipid-soluble drugs have a larger volume of
Drug Absorption
distribution, they are distributed in a larger
Absorption is the process by which a drug passes volume of fat and therefore have a longer half-
from the GI tract to the bloodstream. Several life. Increased body fat acts as a reservoir for
functional changes could be seen in old age like a such lipid-soluble drugs and can also result
decrease in gastric acid production, blood flow to in problems related to drug storage – there
the gut, gastrointestinal motility and mucosal could be accumulation of the drugs in the fatty
absorbing area. There is also an alteration in the tissue and thereby prolonged action. All these
Geriatric Pharmacology 249
changes could put the elderly at a higher risk effects. For example, half-life of certain drugs like
of toxicity from drugs. Hence, these problems diazepam may be increased by as much as four
should be anticipated and necessary dosage times in the elderly. However, the extent of age-
adjustments should be done. related pharmacokinetic changes vary from
person to person. Thus drug dosages should be
Metabolism adjusted and adverse drug reactions minimized
after considering all the above factors.
The aim of drug metabolism is to inactivate the
drugs and make them water soluble so that they
PHARMACODYNAMIC CHANGES
can be easily excreted by the kidneys. Since liver
is the primary site for drug metabolism, age related Age related alterations in the physiological
changes in liver function can affect the process of functions can influence the systemic response to
biotransformation. In the elderly, the drug various drugs. Factors like decreased function of
metabolizing capacity of the liver decreases the smooth muscles of the viscera, decreased
because of the decrease in the liver size, amount baroreceptor sensitivity, impaired postural
of blood flow and hepatic enzyme activity. Many control, altered thermoregulatory responses and
drugs are metabolized more slowly and drugs a reduced cognitive function can all influence the
would remain active for longer periods of time response to a drug.
compared to young adults. Moreover, the oxidative The receptor function may also be blunted, i.e
pathways are inhibited. Hence drugs metabolized the affinity and binding of the drug to the receptor
by oxidation like piroxicam, diazepam, ibuprofen and the cellular functions may be altered in some
and phenytoin have a longer half-life in the tissues due to aging. However, the extent of
geriatric age group. variations depends on the extent of changes in
the physiological functions.
Excretion Other factors that influence response in the
elderly include presence of multiple diseases, poor
The kidneys are the primary organs of drug
diet and poor general health.
excretion from the body. The renal function is
depressed in the elderly because of a decline in
renal blood flow, renal mass and function of renal ADVERSE REACTIONS IN THE ELDERLY
tubules. As a result there is a decrease in GFR, As discussed earlier, elderly are more prone to
tubular secretion and a consequent reduction in adverse effects. The adverse effects which are more
excretion of drugs. Studies have shown drug common in the elderly and need special caution
excretion to be reduced by 35-50 percent due to include—postural hypotension, dizziness,
decrease in GFR. Thus age-related changes in the sedation, urinary retention, constipation, depres-
renal function can result in a significant reduction sion, dehydration, confusion, extrapyramidal
in drug excretion leading to accumulation of drugs symptoms, fatigue and weakness.
and their metabolites in the body. The half-lives
of the drugs get longer, and their clearance Postural hypotension – is a fall in blood pressure
diminishes. Thus reduced renal function should by > 20 mm Hg upon assumption of an erect
be taken into account whenever drugs are posture. Such hypotension causes dizziness and
prescribed in the elderly. syncope because of reduced blood supply to the
The overall effects of the pharmacokinetic brain. This could result in falls and fractures,
changes associated with aging are that drugs cerebral and cardiac infarcts. The older subjects
remain active in the body for longer periods have comparatively less physical activity and
thereby prolonging their effects as well as adverse lower cardiovascular function—all these factors
250 Pharmacology for Physiotherapy
can increase the chances of postural hypotension which reduce heart rate and cardiac output;
in the elderly. Any additional impairment of these diuretics causing dehydration, decreased cardiac
mechanisms by drugs would make them even more output and hyponaturemia and oral antidiabetics
susceptible to postural hypotension. Physio- producing hypoglycemia can all result in
therapists should be aware of it because some of worsening of fatigue and weakness.
the procedures can result in episodes of postural
hypotension and its complications. Depression: Several drugs can cause depression
as an adverse effect. Elderly are as such likely to
Dizziness: Drug induced dizziness is common be depressed due to problems of old age and social
in the elderly. Drugs that produce sedation, altered problems. They are more susceptible to drug
vestibular function, antihypertensives and even induced depression. Symptoms of depression
some analgesics can cause dizziness. Orthostatic include sadness, lack of initiative and interest in
hypotension also results in dizziness. Some the surroundings. These may interfere in their
elderly who already have dizziness are all the ability to assess them.
more susceptible to drug induced dizziness. Apart
from being troublesome to the patient as such, Dehydration: is a common problem in the elderly.
dizziness also increases the risk of falling due to They are more susceptible to this particular side
imbalance. Hence it is necessary to be watchful in effect due to age-related physiological changes like
the elderly for this adverse effect. decrease in lean body mass, increase in fat, and
reduced capacity of the kidney to concentrate
Sedation and confusion: Several drugs produce
urine. Symptoms of dehydration include altered
sedation and confusion as side effects. Elderly
sensorium, dizziness, lethargy, confusion and
people may also be on hypnotics as many of them
weakness which are all vague and may be
may have insomnia. Such sedation may often
misinterpreted for other geriatric problems.
result in confusion and disorientation.
Dehydration may also be due to drugs like
Fatigue and weakness: Most geriatric subjects diuretics, digoxin, vasodilators and laxatives.
have a weaker muscle mass and many are already Dehydration would result in volume depletion,
debilitated. Drugs that produce muscle weakness which in turn may reduce cardiac output. It also
like skeletal muscle relaxants, drugs like β blockers causes weakness and fatigue.
Index